3{40 -keto-2{40 ,3{40 -seco-1{40 -(2{40 )-yne steroidal derivatives, methods for their manufacture, and compounds produced thereby

ABSTRACT

Described herein are novel 3&#39;&#39;-keto-2&#39;&#39;,3&#39;&#39;-seco-1&#39;&#39;(2&#39;&#39;)-yne steroidal structures and processes for their preparation and, in particular, the preferred embodiment thereof, i.e., 5-keto-4,5seco-3-ynes of the estrane, androstane, and pregnane series having physiological activity and being particularly useful as intermediates in preparing pharmacologically active 6- and/or 10substituted steroids. There are described three process aspects, the preferred modes of which are as follows: 1. The first preferred process comprises the preparation of 5keto-4,5-seco-3-yne steroids from 3-keto-4-dehydro steroids having a tertiary carbon at C-3, via the 3hydrocarbonsulfonylhydrazono-4,5-oxido derivative thereof which undergoes fission and rearrangement in situ to form the 5-keto4,5-seco-3-yne structure; 2. The second preferred process comprises reacting any 6- and/or 10- unsubstituted-5-keto-4,5-seco-3-yne in an alkylating medium with a hydrocarbon sulfonate or, preferably, a hydrocarbon halide to form a 6- and/or 10- hydrocarbon substituted-5-keto4,5-seco-3-yne; and 3. The third preferred process comprises treating a 5-keto-4,5seco-3-yne with an alkali metal borohydride to form a 5hydroxy-4,5-seco-3-yne. Also described in detail (including examples) are two methods whereby the preferred 5-keto-4,5-seco-3-ynes of this invention are converted to pharmacologically valuable 6- and/or 10hydrocarbon substituted-3-keto-4-dehydro steroids, e.g., 1. BY REACTION WITH MERCURIC ACETATE AND SULFURIC ACID IN ACETIC ACID; OR 2. BY REACTION WITH MERCURIC OXIDE AND TRIFLUOROACETIC ACID FOLLOWED BY TREATMENT OF THE THEREBY FORMED 3,5-DIKETO-4,5-SECO STEROID WITH POTASSIUM T-BUTOXIDE IN T-BUTANOL.

1 3'-KETO-2,3-SECO-1-(2)-YNE STEROIDAL DERIVATIVES, METHODS FOR THEIR MANUFACTURE, AND CONWOUNDS PRODUCED THEREBY CROSS REFERENCE TO RELATED APPLICATION This application is a continuation-in-part of the copending application Ser. No. 644,761 filed June 6, 1967 of Masato Tanabe, now abandoned.

FIELD OF INVENTION This invention relates to compositions of matter which may be classified in the field of chemistry as 3-keto-2,3-seco-l '(2')-yne steroidal derivatives possessing physiological activity, and which are also particularly valuable as intermediates in preparing other useful steroidal derivatives.

This invention also relates to processes for producing the novel 3-keto-2',3-seco-l'(2)-yne steroids, the basic process of which includes the steps whereby a 1'- keto-2'(3)-dehydro steroid wherein the 3-carbon is disubstituted is converted to the corresponding 1- hydrocarbonsulfonylhydrazono-Z,3-epoxy steroidal derivative, which derivative undergoes fission and rearrangement in situ in the reaction mixture to form a novel 3-keto-2',3'-seco-l(2-)-yne steroidal compound of my invention.

SUMMARY OF INVENTION The invention sought to be patented in its composition of matter aspect resides in the concept of a steroid (including steroids of the pregnane, androstane, estrane, cholestane, and sapogenin series) which possesses a 3-keto-2',3-seco-l(2)-yne system or the corresponding 3-hydroxy-2',3'-seco-l(2')-yne system.

The preferred species of the composition of matter aspect of my invention are the 5-keto-4,5-seco-3(4)- yne steroidal derivatives (particularly of the androstane, estrane, and pregnane series) which possess physiological activity, and which are particularly valuable as intermediates in preparing pharrnacologically active 3-keto-4-dehydro-steroids (many of which are known in the art) substituted at C4 by a lower alkyl, or substituted at C6 by a mono-, di-, or cyclichydrocarbon radical (including substituted hydrocarbon radicals) and/or at 010 by a hydrocarbon radical.

There are several process aspects of this invention. Of these, the invention sought to be patented in its first process aspect resides in the concept of introducing in any sequence into a 1-keto-2,3-dehydro-steroid (i.e., a steroid possessing an afi-unsaturated ketone system) the 3 -carbon of which is disubstituted, an epoxy function across the 2,3'-dehydro double bond, and a hydroazone derivative, preferably a hydrocarbonsulfonylhydrazone derivative, of the l'-keto function, whereby the resultant l-hydrazono-2',3 -oxido-steroid, preferably a l-hydrocarbonsulfonylhydrazono-2,3-oxidosteroid having a tertiary carbon at 03, while in situ in the reaction mixture, undergoes fission between C-2 and G3 with concomitant fragmentation and rearrangement to form the 3-keto-2',3seco-l '-yne steroidal derivatives of the composition-of-matter aspect of this invention.

The invention sought to be patented in the second process aspect of this invention is the concept of further reacting the 3-keto-2',3-seco-l(2')-yne steroidal derivatives which have a replaceable hydrogen on a carbon vicinal to said 3-keto moiety, with an alkylating reagent to form (depending on the relative amounts of reagents used and the reaction conditions employed) mono-, di-, and trivicinally substituted derivatives, including hydrocarbon and substituted hydrocarbon derivatives. v

The invention sought to be patented in the third process aspect of this invention is the concept of further treating said 3-keto-2,3-seco-l '(2)-yne steroid with a reducing agent (e.g., sodium borohydride) so as to reduce the 3-keto function to form a 3 '-hydroxy-2,3 seco-l 2 )-yne-steroidal derivative.

The preferred mode of the first process aspect of my invention is that utilizing a 3-keto-4-dehydro-steroid as the requisite starting l-keto-2',3-dehydro-steroid whereby, upon introduction of a 4,5-epoxy and a 3- hydrocarbonsulfonylhydrazone derivative according to my invention, there is prepared a 3- hydrocarbonsulfonylhydrazono-4,5-oxido-steroid which converts in situ to a 5-keto-4,5-seco-3-ynesteroid, the preferred species of the composition of matter aspect of this invention.

The preferred mode of the second process aspect of this invention includes the step of further reacting any 6- and/or l0-unsubstituted-5 keto-4,5-seco-3'-yne steroids (prepared by the first process aspect) in an alkylating medium such as an alkali metal hydride in an inert solvent (preferably sodium hydride in tetrahydrofuran) and a hydrocarbon halide (e.g. methyl iodide, ethylene dibrornide, pentamethylene dibromide, 2-propenyl bromide) to form, depending on the amounts of reagent and the reaction condition employed, 6-mono-,

lO-mono-, 6,l0-di-, 6,6-di-, 6,6,l0-tri-, and 6,6-cyclichydrocarbon derivatives thereof.

In another species of the preferred mode of the second process aspect, there are included the steps of treating a 5-keto-4,5-seco-3-yne with ethyl formate in the presence of sodium methylate to obtain the corresponding 6-formyl-5-keto-4,5-seco-3-yne which, in turn, upon further treatment with an n-butylthiol in benzene is converted to a 6-n-butylt hiomethylene-5- keto-4,5-seco-3-yne of my invention.

The preferred mode of the third process aspect includes the step of treating a 5-keto-4,5-seco-3-yne with an alkali metal borohydride, e.g., sodium borohydride, to obtain a 5-hydroxy-4,5-seco-3-yne of my invention.

GENERAL DESCRIPTION OF THE PRODUCT ASPECT OF THE INVENTION The invention sought to be patented in its broadest composition of matter aspect is the concept of a steroid (including members of the pregnane, androstane, estrane, cholestane and sapogenin series) which possess a 3'-keto-2',3-seco-l (2)-yne system or the corresponding 3'-hydroxy-2',3-seco-l '(2)-yne system, and which may also possess hydrocarbon substituents having up to 12 carbon atoms on one or more carbon atoms adjacent said 5-keto moiety.

In view of their method of manufacture, as discussed in detail hereinbelow, by my inventive concept, secosteroids of this invention are contemplated as possessing the requisite 3'-keto-2,3'-seco-l(2')-yne system United States Patent [191 Tanabe [11] 3,835,160 [451 Sept. 10,1974

[ 3 '-KETO-2 ',3-SECO-1 '-(2 )-YNE STEROIDAL DERIVATIVES, METHODS FOR THEIR MANUFACTURE, AND COMPOUNDS PRODUCED THEREBY Masato Tanabe, Palo Alto, Calif. Schering Corporation, Bloomfield, NJ.

Inventor:

Assignee:

Filed: June 20, 1967 Appl. No.: 647,315

Related US. Application Data Continuation-impart of Ser. No. 644,761, June 6, 1967, abandoned.

US. Cl... ..260/340.9, 260/239.55 R,

Int. Cl C07d 1 37M Field of Search 260/340.9, 340.5, 345.8, 260/345.9, 488,586 H [5 6] References Cited UNITED STATES PATENTS 9/1964 Cross et al. 260/340.9 9/1968 Nagata 260/340.9 1 H1968 Cross et a1 260/340.9

Primary Examiner-Donald G. Daus Assistant Examiner-James H. Turnipseed Attorney, Agent, or Firm-Mary S. King [57] ABSTRACT Described herein are novel 3-keto-2',3-seco-l'(2)- yne steroidal structures and processes for their preparation and, in particular, the preferred embodiment thereof, i.e., 5-keto-4,5-seco-3-ynes of the estrane, an-

drostane, and pregnane series having physiological activity and being particularly useful as intermediates in preparing pharmacologically active 6- and/or 10- substituted steroids.

Also described in detail (including examples) are two methods whereby the preferred 5-keto-4,5-seco-3-ynes of this invention are converted to pharmacologically valuable 6- and/or 10- hydrocarbon substituted-3-keto-4-dehydro steroids, e.g.,

l. by reaction with mercuric acetate and sulfuric acid in acetic acid; or 2. by reaction with mercuric oxide and trifluoroacetic acid followed by treatment of the thereby formed 3,5-diketo-4,5-seco steroid with potassium t-butoxide in t-butanol.

10 Claims, No Drawings alkylating medium with a hydrocarbon sulfonate CHART A Continued (8) R R p F CECH 0:011

/ /LO I O nozo no in above Chart A, the partial formulae in the first column represent a,B-unsaturated ketone (i.e. l'-keto- 2(3)-dehydro-) systems in normal steroids from which, via my first process aspect, are derived novel seco structures, i.e. the 3-keto-2',3'-seco-l'(2)-ynes represented diagramatically by formulae Ia-If which, in turn, via the second process aspect of my invention, are alkylated to form novel R-substituted-3'-keto-2,3- seco-l(2)-ynes, represented diagramatically by formulae Ia-I'f.

Thus, by means of the second process aspect of our invention, there may be introduced hydrocarbon radicals at C-8 and C10 in 9,1 l-seco-9-keto-l 1(12) ynes of formula I(d) to form IO-R and/or l4-R derivatives defined minimally by formula I'(d).

The preferred species of the composition-of-matter aspect of my invention are the 5-keto-4,5-seco-3(4)- yne steroidal derivatives and their 6 and/or 10- hydrocarbon derivatives. Included within this species are compounds having minimally, the following structural formula:

wherein X is a member selected from the group consisting of ketonic oxygen, (H,BOH), (RB-lower alkanoyloxy), and (H,B-p-toluenesulfonyloxy);

R is a member selected from the group consisting of hydrogen and lower alkyl;

R is a member selected from the group consisting of hydrogen and a hydrocarbon radical having up to 12 carbon atoms;

Y is a member selected from the group consisting of hydrogen,

a polymethylene cyclic radical having from 2 to 8 carbon atoms, (H,B-formyl), and n-lower alkylthiomethylene; and

Z is a member selected from the group consisting of keto,

(W being a member selected from the group consisting of hydrogen, lower alkyl, tetrahydropyranyl, lower alkanoyl, and A being a member selected from the group Included within the term lower alkyl as used in the specification and claims are saturated hydrocarbon radicals having up to four carbon atoms including straight chain and branched radicals such as methyl, ethyl, n-propyl, isopropyl, n-, iso-, and tert.-butyl.

The term hydrocarbon radical having up to 12 carbon atoms as used in the specification and claims encompasses saturated alkyl radicals, both straight chain and branched, having up to 12 carbon atoms such as methyl, octyl, n-dodecyl and like, unsaturated open chain radicals such as 2-propenyl-, and 3 -butenyl; and cyclic hydrocarbon radicals such as cyclo-p'ropylethyl, cyclobutylmethyl, cyclopentyl; as well as, at C-6, spirocyclic hydrocarbon radicals which includes within the spiro ring structure the seco-steroid carbon at C-6, e.g. 6,6-dimethylene (i.e., 6-spiropropane or 6,6-ethylene) 6,6-trimethylene (i.e., -spirobutane), pentamethylene (i.e. spirohexane), and the like.

Typical compounds of the preferred species of the composition of matter aspect of my invention which are defined by above formula I include:

1. 6 and 10 unsubstituted seco-steroidal derivatives of the estrane series (i.e. wherein R and Y are hydrogen) such as:

4,5-Seco-3-estryn-l 7B-0l-5-one and the l7-acetate ester and the l7-tetrahydropyranyl ether thereof (i.e., compounds wherein Z is w C--A,

A being hydrogen, and X being oxygen);

2. 6-unsubstituted-IOB-alkyland 6-unsubstituted IOB-alkylene seco steroidal derivatives (i.e. wherein Y is hydrogen and R is a hydrocarbon radical) of the androstane, pregnane, and cholestane series, such as 4,5-Seco-3-androstyn-l7B-ol-5-one (Z is R is methyl, and X is oxygen) and the 17-acetate ester and l7-tetra-hydropyranyl ether thereof; as well as the 3,8-enol acetate l7-acetate thereof (compound of Example 13A);

4,5-Seco-3-androstyne-5,l7-dione (Z is keto, R is methyl, and X is oxygen),

10B-n-propyl-4,5-seco-3-estrynl 7/3-ol-5-one R is n-propyl, X is oxygen, and Z is l7,20;20,2 l -bis-methylenedioxy-4,5-seco-3- pregnyn-S-one and the ll-keto analog thereof, (i.e.,

wherein X is oxygen, R is methyl, and Z is 4,5-seco-3-pregnyne-5,20-dione, (i.e. wherein X is oxygen, and Z is and 6,6

4,5-seco-3-androstyn-5 l flfl -diol X is "H R is methyl, R is hydrogen, and Z is R are hydrogen, X is oxygen, Y is formyl, and Z is 0TH]? 04H and 6-n-butylthiomethylene-4,5-seco-3-estryn-1 7/3-01- 5-one l7-tetrahydropyranyl ether (a compound wherein Y is n-butyl-thiomethylene);

4. and 6 and lO-diand tri-substituted compounds (ie, both R and Y are other than hydrogen) as exem- 6,6-dimethyl-4,5-seco-3-androstynl 7B-ol-5-one (i.e R is H, R is methyl, Y is and Z is CHZCH=CH7 6,6-Pentamethylene-4,5-seco-3-androstyn- 1 713-01 and the l7-tetrahydropyranyl ether thereof, (i.e. Riis and Z is LHtBJiS, m th l en OW an) aha z is 6,'l0B-di-(2-propenyl)-4,5-seco-3-estryn-17B-ol- 5-one 17-tetrahydropyranyl ether (R is H, X is oxygen, R is 2-propenyl, Y is onion-H1 and Z is 6,6,10B-tri-(2-propenyl)-4,5-seco-3-estryn-1 73-01- 5-one 17-tetrahydropyranyl ether (R is H, X is oxygen,

6-n-butylthiomethylene-l0B-n-todecyl-4,5-seco-3- estryn-l7/3-o1-5-one (R is H, X is oxygen, R' is ndodecyl, Y is n-butyl-thiomethylene and Z is 6,6-dimethy1-17a,20-isopropylidenedioxy-4,5-seco- 3-pregnyn-5-one 6,6-pentamethylene-l 7a,20-isopropylidenedioxy 4,5 -seco-3-pregnyn-5 -one 6,6-dimethyl-l7a,20;20,21-bis-methylenedioxy-4,5-

seco-3-pregnyn-5-one and the 1 l-keto derivative thereof OOH2 CH; Yis --CH;,andZis H1O 0 --oo CHI 0 --0 UTILITY OF 4,5-SECO COMPOUNDS OF THIS INVENTION pounds represented by formulae Ia and Ya, there are formed l-methyl-IOB-hydrocarbon (having up to 12 carbon atoms) substituted-3 keto-l-dehydro steroids;

from seco-compounds represented by formulae lb 5 and Ib, there are derived 7-keto-5-dehydro steroids substituted at C-10 and/or at C-4 by hydrocarbon radicals having up to 12 carbon atoms; 7

from seco-compounds represented by formulae [c and I'c there are derived 6-keto-7-dehydro steroids substituted at 9 and/or at GM by hydrocarbon radicals having up to 12 carbon atoms;

from seco compounds represented by formulae 1d and I'd there are derived 12-keto-9(11)-dehydro steroids substituted at C- 10 and/or C-8 by a hydrocarbon radical having up to 12 carbon atoms;

from seco compounds represented by formulae le and Ie, there are derived 16-keto14-dehydro steroids substituted at C8 by a hydrocarbon having up to 12 carbon atoms,

from the preferred seco compounds of this invention as represented by formulae If and If in Chart A (and by formula I above), there are derived 6 and/or 10- substituted steroidal derivatives which are further discussed hereinbelow.

The 6-unsubstituted 4,5-seco-3-estryn-5-ones and the 4,5-seco-3-androstyn-5-ones of the preferred species of the composition of matter aspect of my invention, in particular those compounds wherein Z is and esters thereof, possess anti-androgenic activity. For example, when tested in the rat via the subcutaneous route, 4,5-seco-3-androstyn-17B-ol-5-one exhibited anti-androgenic activity at dosages about 10 mgm/kilogram and 4,5-seco-3-estryn-17B-ol-5-one exhibited antiandrogenic activity in doses as low as 1 mgm/kilogram body weight. The 6-unsubstituted 4,5-seco-3- androstyn-S-ones and the -unsubstituted 4,5-seco-3- estryn-S-ones are valuable in treating conditions which require an anti-androgen, e.g., in the treatment of benign prostatic hypertrophy in dogs.

The 4,5-seco-3-yne-5-ones such as those defined by formula I (and formulae If and I'f in Chart A) are useful mainly as intermediates via novel processes disclosed hereinbelow for the preparation of new steroid compounds as well as known, pharmacologically valuable steroids of the pregnane and androstane series including l. 6- uns ubs tituted-l0fi-liighefalkyl analogs or the pregnane and androstane series such as described in US. Pat. Nos. 3,309,386 and 3,309,387, and in French Patent No. 1,146,640.

Of these, by way of example, the A-ring-unsaturated- IOB-n-propyl-androstenes (i.e., A-ring unsaturated-19- vinyl-androstenes) as exemplified by l0B-n-propyl-4- estrene-l7B-ol-5-one (prepared via the novel compounds and processes of this invention as described in Examples 16, 20, and 21) are described in US. Pat. No. agents.

2. 6-spiroalkane derivatives (i.e., 6,6-cyclicpolymethylene derivatives) of steroids of the androstane and estrane series such as described and claimed in South African Patent No. 66/5332 and Netherlands Application 66,03861, and the 6-spiroalkane pregnanes in Netherlands Application Nos. 66,0386] and 3,309,386, useful as gonadotropin-inhibiting- 1,066,729, and in drostane and pregnane series some of which are known useful compounds, such as 4,5-seco-9-estryn-l713-01- 3,5-dione l7-acetals described in Belgian Patent No. 592,003, a useful intermediate to .prepare l9-nor-9-dehydro-testosterone acetate; and 4,5-secol9-nor-9-pregnene-3,5,20-trione described in US. Pat. No. 3,155,660 as a useful intermediate in the preparation of l9-nor-9-dehydroprogesterone.

The value of the 3'-keto-23-seco-l '(2')-ynes of my invention as intermediates, is based upon my discovery that my novel 4,5-seco-5-keto-3-ynes may be readily ring closed to form normal 3-keto-A -steroid compounds via either a direct, one-step, method by the action of mercuric acetate and sulfuric acid in acetic acid as solvent at reflux temperature for about two hours; or, alternatively via a two step procedure wherein a 5-keto-4,5-seco-3-yne of the general formula I above upon treatment at room temperature for about an hour with mercuric oxide and trifluoroacetic acid in aqueous dioxane as solvent is converted to another class of 4,5- seco compounds (some species of which are known in the art), i.e., the 3,5-diketo-4,5-seco steroids which, upon treatment with potassium tert.-butoxide in butanol, at reflux temperature for about three hours, are

ring closed to a steroid of normal configuration. Both of these ring closure processes wherein my novel compounds are the requisite starting compounds, are illustrated diagramatically below via flow diagram, A being the remaining portion of a steroid molecule of the androstane and pregnane series:

Ring Closure Process A:

/ R (A) 1 W Ring Closure Process B:

ll CH O CH:

Examples 4-(Procedure 1), 12B, 17 and 33D of this application illustrate the novel ring closure process A. In these examples, 4,5-seco-3-androstyn-l7B-ol-5-one, 4,5-seco-3-androstyn-5 l 7-dione, 4,5-seco-3-estrynl7B-ol-5-one l7-acetate and 6-n-butylthiomethylenc- 4,5-seco-3-androstyn-l7B-ol-5-one are each treated with mercuric acetate and sulfuric acid in aqueous dioxane to form, respectively, testosterone, 4- androstene-3 ,1 7-dione, l9-nor-testosterone acetate. and 6-n-butylthiomethylene testosterone l7-acetatc.

Examples 4 (Procedure2), 6, 9,11,14,15, 21, 23, 25 (B-F), 29 (B-E) and 30 (B-E), 32 (CF) and 34 (B-D) of this application illustrate ring closure Procedure B. In these examples, each of the following compounds of my invention:

1. 4,5-Seco-3-androstynl 7B-ol-5-one 2. 6,6-Dimethyl-4,5-seco-3-androstyn-17B-ol-5-one l7-methyl ether 3. 6,6-Di-(2'-propenyl)-4,5-seco-3-androstyn-17B- ol-5-one 4. 6,6-Pentamethylene-4,5-seco-3-androstyn- 1 73-01- 5.-one

5. 6,6-Dimethyl-4,5-seco-3-androstynl 7B-ol-5-one l7-acetate 6. l0B-n-Propyl-4,5 -sec'o-3-estryn-l 7B-ol-5-one,

7. 6,l0-Di-(2-propenyl)-4,5-seco-3-estryn-l7B-ol- 5-one 8. 6,6, l 0-Tri (2 -propenyl)-4,5-seco-3-estryn-17B- ol-5-one l7-tetrahydropyranyl ether 9. 6-n-Butylthiomethylene-l0-n-dodecyl-4,5-seco-3- estrynl 7B-ol 5-one l 0; 6,6-Dimethyl-17a,20-isopropylidenedioxy-4,5- seco-3-pregnyn-5-one ll. 6,6-Pentamethylene-l701,20-

isopropylidenedioxy-4,5-seco-3-pregnyn-5-one l2. 6,6-Dimethyll 7a,20;20,2 l -bis-methylenedioxy- 4,5-seco-3-pregnyn-5-one and the ll-keto derivative ,thereof,

upon reaction with Mercuric oxide and trifluoroacetic acid in aqueous dioxane are converted to the corresponding 3,5-diketo-4,5-seco-derivative, respectively, i.e.

1. 4,5-Seco-3-androstanl 7B-ol-3,5-dione 2. '6,6-Dimethyl-4,5-seco-3-androstan l 7B-ol-3 ,5- dione l7-methyl ether 3. 6,6-Di-( 2-propenyl )-4,5-seco-3-androstan- 1 7B- ol-3,5-dione 4. 6,6-Pentamethylene-4,5-seco-3-androstan- 1 73-0]- 3,5-dione 5. 6,6-Dimethyl-4,5-seco-3-androstan-l7B-ol-3,5- dione l7acetate 6, 10B-n-Propyl-4,5-seco-3-estran-17B-ol-3,5-dione 7. 6, l 0B-Di-( 2'-propenyl )-4,5-seco-3-estran- 1 713-01- 3,5-dione 8. 6,6,lOB-Tri-(Z -propenyl)-4,5-seco-3-estran-17B- ol-3,5-dione l7-tetrahydropyranyl ether 7 9. 6n-Butylthiomethylenel 0-n-dodecyl-4 ,5 -seco-3- estranl 7B-ol-3 ,S-dione 10. 6,6-dimethyll 7a,20-isopropylidenedioxy-4,5- seco-3-pregnane-3,5-dione l l. 6,6-Pentamethylene-l:,20- isopropylidenedioxy-4,5-seco-3-pregnan-3,S-dione and 7 of the foregoing compounds in turn upon treatment 6,6-Pentamethylene- 1 701,20-

isopropylidenedioxy-4-pregnene-3-one which upon hydrolysis in acetic acid is converted tothe 20,2l-diol which, in turn, is oxidized at C- to yield 6,6- pentamethylenel 7a-hydroxyprogesterone 6- spirocyclohexane-l 7a-hydroxyprogesterone) and 12. 6,6-Dimethyll 7a,20;20,2 1 -bis-methylenedioxy- 4-pregnene-3-one and the ll-keto derivative thereof (each of which upon hydrolysis in aqueous acetic acid followed by re-esterification with acetic anhydride in pyridine yields 6,6-dimethyl-4-pregnene- 1 711,2 1 -diol-3 ,20-dione and 6,6-dimethyl cortisone.

Similarly, in Examples 35-43 are described the preparation of lOB-n-propyl-4,5-seco-3-yne-5-ones and 6,6- ethylene-4,5-seco-3-yne-5-ones (i.e., 6- spirocyclopropane-4,5-seco-3-yne-5-ones) of my invention and the conversion of my 4,5-seco-3-ynes to the therapeutically valuable IOB-n-propyland 6,6- ethylene-steroids of the androstane, estrane, and pregnane series disclosed and claimed in the aforementioned patents.

General Description of the Process Aspects of this Invention First Process Aspect The invention sought to be patented in its broadest process aspect is based upon my discovery that when there is introduced into a l'-keto-2',3'-dehydro steroid (i.e. a steroid possessing an a,B-unsaturated keto system) having a tertiary carbon at the 3-position, both a hydrazone derivative and preferably a hydrocarbonsulfonylhydrazone derivative of the lketo and an epoxy function across the 2',3-double bond, the l-hydrazono-2,3'-epoxy steroidal derivative thereby formed undergoes fission between C-2' and C-3' with concomitant fragmentation and rearrangement in situ in the reaction mixture, either immediately, or upon standing at room temperatures, or upon heating at moderate temperatures in the range of from about 35C to about 75C, to form a novel class of compounds, i.e., the 3'-keto-2,3-seco-l(2')-yne steroids of the composition of matter aspect of this in- 'vention. l have discovered, further, that this reaction is of a general nature, and that formation of a lhydrocarbonsulfonylhydrazono-2,3' -epoxy derivative moieties will result in fission between C-2' and C-3' and the formation of a 3-keto-2,3-seco-l'(2')-yne steroid, provided the carbon at C-3' is tertiary.

Thus, (with reference to Chart A) when each of la,17a-dimethyl testosterone (i.e. A -3-keto) 3- acetoxy-3,5-cholestadiene-7-one (i.e., A -7 keto), 3B- acetoxy-5B-hydroxy-7,22-lumis-tadiene-6-one (i.e. A 6-keto), 9(1 1)-dehydrohecogenin-3-acetate (i.e. A l2-keto), 3B-acetoxy-l4-androstene-l6-one (i.e. A- l6-keto), and testosterone (A -3-keto) are converted to the corresponding hydrazone-epoxy derivatives, e.g.

3-p-toluene-sulfonylhydrazonol ,2-oxidol a, 1 7adimethyl-androstan- 1 713-01,

3-acetoxy-5,6-oxido-7-p-toluenesulfonylhydrazono- 3-cholestene,

3,8-acetoxy-5B-hydroxy-6-ptoluenesulfonylhydrazono-7,8-oxido-22-lumistene,

9,1 l-oxido-hecogenin 3-acetate 12-p-toluenesulfonylhydrazone,

l4,15-oxido-l6-p-toluenesulfonylhydrazono androstane and 3-p-toluenesulfonylhydrazono-4,5-oxidoandrostanl 7B-ol,

fission and rearrangement of each of the foregoing derivatives occurs and there are formed seco-steroid compounds of my invention, e.g.

l l 7a-dimethyl-l ,2-seco-3-androstyn-l 7/3-ol-1-one 3-acetoxy-5,6-seco-3-dehydro-7-cholestyn-5-one 3B-acetoxy-5B-hydroxy-7,8-seco-22-dehydro-6- lumistyn-8-one,

9,1 l-seco-22a,25a-l 1-spirostyn-3B-ol-9-one 3-acetate 3,8-acetoxy- 1 4, l 5-secol 6-androstyn-l 4-one and 4,5-seco-3-androstyn-17,8-01-5-one, respectively.

The preferred mode of carrying out my process is that wherein a 3-keto-A steroid is utilized as starting compound (e.g., testosterone) and there is prepared a 4,5-seco-5-keto-3-yne steroid of this invention (e.g., 4,5 -seco-3-androstynl 7B-ol-5-one).

Discussed in detail below is the manner of carrying out the physical embodiments of the preferred species of the process aspect of this invention, it being understood that, in similar manner, any a,B-unsaturated keto steroid can be reacted by my process to form a 3-keto- 2',3'-seco-l '(2)-yne steroid of this invention.

In carrying out my process, known techniques for preparing the epoxy and hydrazone derivatives are used. it is immaterial, furthermore, whether the epoxy function or hydrazone derivative is introduced first into the molecule, although I have found it more convenient to first prepare the epoxy derivative, or to use a known a-epoxy-B-keto steroid as a starting compound.

Thus to prepare 4,5-seco-3-androstyn-l 7B-ol-5-one compound I, R =CH or to prepare 4,5-seco-3-estrynl7B-ol-5-one (compound I, R is hydrogen) by my process, one can utilize either one of the sequences of reactions shown in below Chart B, i.e. l) by first treating 'testosterone (or l9-nor-testosterone) with a known epoxidizing reagent (such as alkaline hydrogen peroxide) followed by treatment of the thereby formed 4,5-oxidoandrostanl 7B-ol3-one (or 4,5 -oxido-estranl 7B-ol- 3-one) with a hydrocarbonsulfonylhydrazine (preferaof any l'-keto-2',3'-dehydro system present in the steroid molecule, e.g. such as the 3-keto-A 3-keto-A 7-keto-A l2-keto-A "-6-keto-66 and l6-keto-A bly p-toluenesulfonylhydrazine) in a lower alkanol according to standard procedures for making hydrazone derivatives of ketones or (2) alternatively, by first reacting testosterone (or l9-nor-testosterone) with p-toluenesulfonylhydrazine in ethanol followed by treatment of the thereby formed 3-p- 'such as nichlorperben zoic acid in methylene chloride.

The steric configuration of theepoxy group at C-4,5 is immaterial to my process. Both the 4a ,sa 'bxi'ab afid the 4B,5B-oxido intermediates Zab undegp fissig rgnd rearrangement to form the 4,5-seco-5-keto-3-ynes of formula I.

In both procedures l and 2) shown below in Chart B, the reaction mixtures in which intermediary products 2 ab (and thence seco steroids I) are being formed are stirred at room temperature for relatively long periods of time, i.e. 9 hours in procedure (1) and 17 hours in procedure (2). When carrying out my process for the first time on an a,B-unsaturated steroid, it is desirable to take aliquots of the reaction mixture at intervals to determine via thin layer chromatographic and spectral data the progress of the reaction as evidenced by the amount of starting products (la) or (1b) remaining in the reaction mixture,

Rr l W sequency 0H CH3 I sequencxA R I g is converted to 3,4-seco-3-androstyn-l'7Bol-5-one (compund l, R is methyl) there are used techniques similar to those known in the art. Thus, to prepare the hydrocarbonsulfonylhydrazone derivatives, e.g. product lb, a steroid having a keto moiety is usually dissolved in a lower alkanol to which is added at least a molar equivalent of a hydrazine and usually a hydrocarbonsulfonylhydrazine, preferably p-toluenesulfonylhydrazine and methanesulfonylhydrazine. Other sulfonylhydrazines may also be employed, such as ethane-sulfonylhydrazine, benzenesulfonylhydrazine, napthalene-B-sulfonylhydrazine, sulfonylhydrazine, ortho-toluenesulfonylhydrazine, metatoluenesulfonylhydrazine, and, 3,4-xylenesulfonylhydrazine.

acid, and the like, in an inert solvent.

RH; H GEL cluding, in particular, column and thin layer chromatography.

In carrying out the basic steps of my process as described in above procedures (1) and (2) (chart B) whereby testosterone (compound A wherein R is CH l have found it desirable when carrying out my process to utilize a per acid (e.g., perbenzoic acid) in an inert solvent, (e.g., methylene chloride) when introducing the epoxy function after the hydrazone derivative has been made; whereas alkaline hydrogen peroxide is my choice of epoxidizing reagent when introducing the epoxy group prior to the hydrazone derivative.

It is usually preferable to carry out my process under an atmosphere of an inert gas, such as argon or nitrogen. Second Process Aspect whereby groups are introduced on carbons vicinal the B-carbon of the starting l-keto-2,3-dehydro steroid which, in the case of the preferred species of this invention relates to the intro duction of groups at C-6 and/or 010.

Described above is a preferred mode of the basic first process aspect of my invention whereby a 3-keto-4- dehydro-steroid (e.g., testosterone and l9-nortestosterone) upon epoxidation across the N-bond and preparation of the p-toluenesulfonyl-hydrazone derivative of the 3-keto, is converted to form a 5-keto-4,5- seco-3-yne, product I, of my invention (e.g. 4,5-seco-3- androstynl 7B-ol-5-one and 4,5-seco-3-estryn- 1 713-]- -one, respectively).

In a second process aspect of my invention, 4,5-seco- 3-yne-5-ones (prepared by the above described first process aspect), are further reacted in an alkylating medium, (such as those utilizing sodium hydride in tetrahydrofuran, butyl lithium in ethylene glycol dimethyl ether, or an alkali metal alkoxide in alkanol, e.g., potassium tert. butoxide is butanol or sodium methoxide in benzene, with a hydrocarbon sulfonate or, preferably, hydrocarbon halide including alkyl halides, aralkyl halides, alkenyl halides, e.g., methyl iodide, whereby (depending upon the quantity of reagent and the reaction conditions employed, in particular, temperature and length of reaction) any replaceable hydrogens on 06 and/or C-lO are substituted by the hydrocarbon radical of said hydrocarbon halide (e.g., methyl) and there may be formed, for example, 6-methyl, 6,6-dimethyl, lO-methyl, 6,10-dimethyl or 6,6,10-trimethyl analogs of the starting 4,5-seco-3-yne-5-ones.

In carrying out the alkylating reactions of the second process aspect of my invention, it is preferable to protect any groups which might enter into a reaction with the reagents being employed. Thus, prior to subjecting the seco steroids to an alkylating agent according to this second process aspect of my invention, any secondary hydroxy groups present, such as at CU, are protected either by esterification thereof or by preparation of the tetrahydropyranyl ether function.

Pregnane compounds having a cortical side chain at C-l7 are desirably converted to a l7a,2();20,2l-bismethylendioxy function, or to 17,2l-acetonide derivatives. Similarly, in l7a-hydroxyprogesterone compounds, the -keto group is desirably reduced to the corresponding 20-carbinol and the l7a,20-diol thereby formed converted to the corresponding 17,20- acetonide prior to alkylation of a 6 and/or 10- unsubstituted-4,5-seco-5-keto-3-yne to a 6- and/or 10- hydrocarbon substituted 4,5-seco-5-keto-3-yne of my invention.

The second process aspect of my invention is based upon my discovery that, by utilizing alkylating techniques, hydrocarbon substituents may be introduced into the 6 and/or 10 positions of my novel 4,5-seco-5- keto-3-yne steroidal derivatives and that the C-lO tertiary hydrogen (when present) will alkylate prior to the secondary hydrogens at C-6. Furthermore, introduction of the second hydrocarbon group at C-6 usually requires forcing conditions (i.e. excess reagent, higher temperatures and longer reaction time). Thus, by varying the conditions under which the physical embodiment of the second process aspect is carried out, there may be obtained a lO-mono-, 6-mono-, 6,l0-di-, or a 6,6,lO-trisubstituted 4,5-seco-6-keto-3-yne of my invention.

Since, by my process, the carbon at C-lO undergoes alkylation prior to the carbon at C-6, the lO-alkyland 10-alkylene derivatives having up to 12 carbon atoms are conveniently prepared by the alkylation process aspect of my invention by reaction of a l9-nor-4,5-seco of formula I, i.e. 4,5-seco-3-estryn-l7Brol-5-one (after protection of the l7-hydroxyl group by preparation of an ester of tetrahydropyranyl ether thereof) with a molar equivalent of an alkyl halide, e.g., propyl iodide, in the presence of an alkylating medium, e.g., sodium hydride in tetrahydrofuran, under mild conditions, e.g., at room temperature for about 16 hours followed by a short period (1.5 hours) at about 60C, whereby l0-npropyl-4,5-seco-3-androstyn-l7B-ol-5-one is formed (Example 20).

When starting with a 6 and IO-unsubstituted 4,5-seco-5-keto-3-yne of my invention, e.g., 4,5-seco- 3-estryn-l7B-ol-5-one, by using an excess of a hydrocarbon halide, together with heat and longer reaction times, there can be made 6,l0'diand 6,6,l0-trisubstituted compounds. For example, 4,5-seco-3- estryn-l7B-ol5-one l7-tetrahydropyranyl ether in refluxing tetrahydro-furan in the presence of at least molar equivalents of sodium hydride to which has been added a large molar excess of 2-propenyl bromide will, after 17.5 hours be converted to 6,10-di- (2 -propenyl )-4,5-seco-3-androstynl 7/3-ol-5 -one l7-tetrahydro-pyranyl ether (Example 22A), whereas additional halide reagent, i.e., 2-propenyl bromide, is required plus a longer period of heating time, e.g., 72 hours at reflux temperature, in order to introduce the third 2'-propenyl group to obtain 6,6,l0-tri- (2-propenyl)-4,5-seco-3-androstynl 7B-ol-5-one l7-tetrahydro-pyranyl ether (Example 24A).

By combining varying alkylating reagents and techniques, there can be obtained derivatives having different substituents at C-6 and C-lO. Thus, 4,5-seco-3- estryn-l7B-ol-5-one (wherein the l7-hydroxy is protected by a l7-tetrahydropyranyl structure) upon treatment with sodium ethoxide in benzene and ethylformate at low temperatures is converted to 6-formyl-4,5- seco-3-estryn-l7B-ol which, in turn, upon treatment in benzene with n-butyl-thiol in the presence of p-toluenesulfonic acid at reflux temperatures for short periods of time (e.g. l-3 hours) will form the enol-thiol ether derivative of the 6-formyl group to produce 6-nbutylthiomethylene-4,5-seco-33strynl 7B-ol-5-one (Example 25B). Further treatment of the foregoing 4,5-seco steroid in a strongly basic alkylating medium (e.g. potassium tert.-butoxide in tert. butanol with an excess of dodecyl iodide under forcing conditions, i.e. at reflux temperature for 36 hours) according to the second process aspect of this invention is converted to 6-n-butylthiomethylene-lO-dodecyl-3-androstyn-17B- ol novel steroidal derivatives of my invention.

In the foregoing procedure, the method of 6- formylation followed by enolization at C-6 via butylthiol, provides a means of introducing'a novel substituent at C-6 prior to alkylation at C10 in a l9-nor steroid to produce a lO-higher alkyl analog of the 4,5-seco-5- keto-3-ynes of my invention.

When utilizing methyl iodide as the alkylating hydrocarbon halide reagent, and an excess of reagent is used with respect to the molar quantity of starting steroid, all available hydrogens at C-6 and C10 will alkylate with ease. Thus, when 4,5-seco-3-estryn-l7B-ol-5-one l7-acetate and the IO-methyl analog thereof (i.e., 4,5- seco-3-androstyn-l7B-ol-5-one l7-acetate) are each treated with an excess of methyl iodide in an alkylating medium such as butyl lithium in ethylene glycol dimethyl ether at room temperature for only 45 minutes, there is produced the 6,6,l0-trimethyl derivative, i.e. 6,6,10-trimethyl-4,5-seco-3-estryn;l 7B- ol- 5-one l7-acetate (identical to 6,6-dimethyl-4,5-seco-3- androstyn-l7B-ol-5-one l7-acetate), Examples 15 A and 18.

Similarly, 4,5-seco-3-estryn-l7B-ol-5-one and the IO-methyl analog thereof when treated in an alkylating medium such as sodium hydride in tetrahydrofuran with an excess of methyl iodide, will, upon stirring at 50C for about 15 hours, be converted to the 6,6,l-trimethyl-l7-methyl ether derivative, e.g., 6,6,- lO-trimethyl-4,5-seco-3-(estryn)17B-ol-5-one l7- methyl ether (also named 6,6-dimethyl-4,5-seco-3- estryn-l7B-ol-S-one l7-methyl ether) in admixture with some of the methyl ethinyl analog, i.e. 4,6,6- trimethyl-4,S-seco-androstanl 7B-ol-5-one l7-methyl ether (Example 19).

Similarly 4,5-seco-3-pregnynl 7a,20-diol-5-one 17,20-acetonide, 4,5-seco-3-pregnynl 7a,2 l -diol- 5,20-dione l7,20;20,2l-bis-methylene dioxide and the ll-keto derivative thereof in an alkylating medium,

such as sodium hydride in tetrahydrofuran upon treatment with an excess of methyl iodide at 50C for about 10-15 hours are each converted to the corresponding 6,6-dimethyl analogs, i.e., 6,6-dimethyl-4,5-seco-3- pregnyne-l7a,20-diol-5-one 17,20-acetonide, 6,6- dimethyl-4,5seco-3-pregnynel 7a,2 l -diol-5 ,20-dione l7,20;20,2l-bis-methylenedioxide and the l l-keto derivative thereof (Examples 29, 32, 34). When the acetonide and bis-methylenedioxy protective groups in the side chain at C-l7 of the foregoing 4,5-secopregnanes of my invention are hydrolyzed in an acidic medium such as acetic acid, there is obtained respectively 6,6-dimethyl-4,5-seco-3-pregnyn-l7a,20-diol 5-one (which upon oxidation with dicyclohexyldicarbodiimide and dimethylsulfoxide is converted to the corresponding 20-keto analog), 6,6-dimethyl 4,5-seco- 3-pregnyn-l7a,2l -diol-5,20-dione and 6,6-dimethyl- 4,5 -seco-3-pregnyne- 1 704,2 1 -diol-5 ,l l,20-trione. The second process aspect of my invention provides a convenient means for introducing a spiroc'ycloalkane derivative at C-6 into my novel 4,5-seco-5-keto-3-ynes. Thus, reaction of each of 4,5-Seco-3-androstyn-l 7B-ol- 5-one l7-tetrahydropyranyl ether, 4,5-Seco-3-pregnynl7a,20-diol-5-one 17,20-acetonide, and 4,5-Seco-3- pregnyne-l 7a,2l-diol-5,l 1,20-trione l7,20;20,2 l-bismethylenedioxide with sodium hydride in tetrahydrofuran followed by pentamethylene dibromide for about 16 hours at 70C will yield, respectively, 6,6- Pentamethylene-4,5-seco-3-androstynl 7a-ol-5-one l7-tetrahydropyranyl ether, 6,6-Pentamethylene-4,5- seco-3-pregnynel 7a,20-diol-5-one 17,20-acetonide and 6,6-Pentamethylene-4,5-seco-3-pregnyne-1704,21- diol-5,l 1,20-trione l70z,20;20,2 l -bis-methylene dioxide (Examples 10A, 30).

Third Process Aspect By means of a third process aspect of my invention, the 5-hydroxy-4,5-seco-3-ynes of my invention are derived from the corresponding 5-ones, in turn, prepared as described in the first two process aspects of my invention. The third process aspect of my invention comprises treating a 4,5-seco-5-one, e.g., 4,5-seco-3- androstynl 7a-ol-5-one, and l7oz,20;20,2 1 -bismethylene-dioxy-4,5-seco-3-pregnyn-5-one, with a reducing agent which will not effect the alkinyl group at C-3, including alkali metal borohydrides such as lithium borohydride, potassium borohydride and, preferably, sodium borohydride in methanol, and the 5keto is reduced to a S-hydroxy function and there is formed respectively, 4,5-seco-3-androstyne-5,l7a-diol and 17- a,20;20,2 l -bis-methylenedioxy-4,5-seco3-pregnyn-5- ol.

Any reactive keto substituents present in the molecule are preferably protected prior to reduction with sodium borohydride by preparing functional derivatives thereof, such as dialkyl ketals, cyclic alkylene ketals, enol ethers and enol esters or, when they are present in the C-20 pregnane cortical side chain by preparing acetonide derivatives, e.g. 170:,2 l -acetonides or 17- a,20;20,2 l -bis-methylenedioxy derivatives.

The S-hydroxy derivatives of my invention can be esterified utilizing known techniques, e.g., by lower alkanoic acid anhydride in pyridine or a hydrocarbon carboxylic acid halide, e.g., benzoyl chloride or a sulfonic acid chloride in pyridine. Thus 4,5-seco-3-androstyn- 5 l 7a-diol-l 7-tetrahydro-pyranyl ether and l7a,20;20- ,2 l bis-methylenedioxy-4,5-seco-3-pregnyn-5-ol upon treatment with either acetic anhydride or ptoluenesulfonyl chloride will yield the corresponding 5-ester, i.e., the S-acetate and 5-p-toluenesulfonate, respectively.

In general, when carrying out any of the process aspects it is preferable to introduce into the normal steroid molecule prior to fission and rearrangement by the first process aspect of this invention, any protective groups which will be needed in any of the three process aspects of this invention. When the 4,5-seco-5-keto-3- yne steroidal derivatives thus prepared are to be utilized as intermediates for preparing pharmacologically valuable steroids as discussed hereinabove, the protective groups are conveniently retained until after ring closure of my seco compounds to a normal steroid structure. Alternatively, when the seco compounds are to be used per se, the protective groups, e.g., esters,

ethers, acetonides, and bismethylene dioxy functions, can be removed after any one of the processes of this invention.

The above is a description of my invention concept and of physical embodiments thereof exemplifying the manner of making and using my invention. It is to be understood that my invention is not to be construed as limited to the above disclosed but as also encompassing equivalents thereof obvious to one skilled in the art of the class of chemistry to which this invention pertains.

EXAMPLE 1 4,5-Seco-3-andr0stynl 7B-ol-5-one A. To a solution of 13.8 g. of 4,5-oxido-androstanl7B-ol-3-one in 1350 ml. of ethanol add 9 g. of p-toluenesulfonyl-hydrazine. Stir the reaction mixture for 2 hours at room temperature then pour into 3 liters of a saturated aqueous sodium chloride solution. Extract the aqueous mixture with three, liter portions of chloroform, then wash the combined chloroform extracts with 3 liters of a 5 percent sodium bicarbonate solution followed by 3 liters of 2N hydrochloric acid, and finally with 3 liters of water. Dry the chloroform solution of sodium sulfate, filter and evaporate in vacuo to a residue. Dissolve the residue in benzene and chromatograph on acid-washed alumina. Elute first and benzene followed by ether-benzene (1:4). Evaporate the combined benzene eluates to a residue comprising 4,5-seco-3-androstyn-l7B-ol-5-one (2 g.). Evaporate the combined ether-benzene eluates to a residue comprising 4,5-seco-3-androstyn-l7B-ol-5 one (9.5 g.).

Purify by sublimation at C in vacuo (10 mm Hg). [01],, 29'hm3X 2.9, 3.0, 4.74, and 5.9 u; nmr

6.4 r (multiplet- C-l7H), 8.0 -r (C 17-01-1), 8.90 r (C 19-31-1), and 9.2 -r (C 18-311).

B. Alternatively the compound of this example is also prepared utilizing methanesulfonylhydrazine as reagent as follows.

To a solution of 200 mg. of 4,5-oxido-androstan-17B- ol-3-one in 30 ml. of absolute ethanol add 80 mg. of methanesulfonylhydrazine. Stir the reaction mixture at 'room temperature under nitrogen for 9 hours then evaporate in vacuo to a residue. Chromatograph the residue on 20 g. of alumina, eluting with percent ether-in-benzene to obtain 4,5-seco-3-androstyn-l7B- ol-5-one (104 mg.) which is identical to the compound produced in above Example 1A. as determined by thinlayer chromatography (chloroform-ethyl acetate (1:1) silica gel GF) and by infrared spectral analysis.

EXAMPLE 2 4,5 -Seco-3 -androstyn-1 7,8-01-5-one (Via Alternate Starting Compound) A. 4-Androsten-17B-ol-3-one 3-p-toluenesulfonylhydrazone 1. To 100 mg. (0.35 mmoles) of testosterone (4-androsten-17B-ol-3-one) in 15 ml. of absolute ethanol add 60 mg. (0.37 mmoles) of p-toluenesulfonylhydrazine. Stir the reaction mixture under an atmosphere of nitrogen for 15 hours at room temperature then pour into 75 ml. of ice water. Filter the reaction mixture and wash the residue with about ml. of 1N hydrochloric acid, two 10 ml. portions of 5 percent aqueous sodium bicarbonate, and then with 10 ml. of water to obtain 4-androsten-17B-ol-3-one 3-p-toluenesulfonylhydrazone (60 mg.). mp. 124-139C. dec., frothing, (darkens at 130C.)

tmax""""" 259 my. 6 17,500

kmax 2.8 p. (NI-l); 3.1 u (OH); 6.15 p. (CXC); 6.25 p. (N-H) 2. Alternatively, the compound of this example is prepared as follows:

Reflux a mixture of 5 gm. (1.74 X 10 moles) of testosterone and 3.55 gm. (1.91 X 10 moles) of p-toluene-sulfonylhydrazine in 125 ml. of absolute ethanol for 1.5 hours. Cool the reaction mixture and pour into 700 ml. of ice water. Extract the aqueous mixture with a one liter portion and then two 500 ml. portions of methylene chloride. Wash the combined methylene chloride extracts with two 400 m1. portions of 1N hydrochloric acid, followed by 400 ml. of 5 percent aqueous sodium bicarbonate, and finally with 400 ml. of saturated sodium chloride solution. Dry the methylene chloride solution over sodium sulfate, then concentrate under reduced pressure to 300 ml. comprising 4-androsten-1 7B-ol-3-one 3-p-toluene-sulfonylhydrazone in chloroform. This concentrated solution is used without further purification in following Example 2B rs qeairand xm 769 -9 To the concentrated methylene chloride solution 4-androstenl 7/3-o1-3-one 3-p-toluenesulfonylhydrazone (prepared as described in Example 2A-2) add 4.15 g. of 80 percent m-chloroperbenzoic acid (1.91 X 10 moles). Stir the reaction mixture for 17 hours at room temperature under an atmosphere of nitrogen. Wash the solution with two 400 ml. portions of 5 percent aqueous bisulfite, 400 ml. of 5 percent aqueous sodium bicarbonate and finally, with 400 ml. of saturated sodium chloride. Dry the methylene chloride solution over anhydrous sodium sulfate and evaporate in vacuo to a residue comprising 4,5-seco-3-androstyn- 17B-ol-5-one (5.8 g.).

Purify this residue by chromatography on 150 g. of alumina, eluting with 5 percent ether in benzene. Evaporate the combined eluates in vacuo to a residue comprising 4,5-seco-3-androstyn-17B-ol-5-one (1.7 g.) which is identical to the compound produced in Example 1A, as determined by thin-layer chromatography and by infrared spectral analyses.

EXAMPLE 3 9,1 1-Seco-22a,25a-1 1-spirostyn-3B-ol-9-one 3-acetate A. 9(11)-Dehydrohecogenin l 2-p-to1uenesulfonylhydrazone Add 10 g. (2.2 X 10' moles) of 9(1l)- dehydrohecogenin 3-acetate, 7.5 g. (4 X 10' moles) of p-toluenesulfonylhydrazine and 0.75 g. of p-toluenesulfonic acid to 800 ml. of absolute ethanol. Reflux the resulting solution for 60 hours under an atmosphere of nitrogen. Cool the reaction mixture and pour it into 3 liters of water. Filter the aqueous mixture and wash the residue with 1N hydrochloric acid followed by S per cent aqueous sodium bicarbonate and finally, with saturated sodium chloride. Dry the washed precipitate in vacuo to yield 9(1l)-dehydrohecogenin 3-acetate 12- p-toluenesulfonylhydrazone.

Purify by recrystallizing twice from methylene chloride-methanol. mp. 270273C. (dec.) )t,,,,,,, 3.05 t, 5.83 ,u., 6.23 1.,815 pt, 8.65 ,l.:., 12.4 a.

3-acetate 1 Dissolve 15 g. of 9(11)-dehydrohecogenin 3-acetate l2-p-toluenesulfonylhydrazone in 1800 ml. of methylene chloride and add 5.6 g. (2.56 X 10' moles) of percent m-chloroperbenzoic acid. Stir the reaction mixture at room temperature for 24 hours under an atmosphere of nitrogen. Wash the methylene chloride solution with 500 ml. of 5 percent aqueous sodium bisulfite, 500 ml. of 5 percent aqueous bicarbonate and Finally, with 500 ml. of saturated sodium chloride. Dry the methylene chloride solution over anhydrous sodium sulfate then evaporate in vacuo to a residue comprising 9,l 1-seco-22a,25a-1 1-spirostyn-3B-ol-9-one 3-acetate.

Purify by chromatography on 450 g. of alumina eluting with 10 percent ether in benzene. Evaporate the combined eluates to a residue, then crystallize the residue from methanol. m.p. 203.5207.5C. lt 3.05 p. (C CH), 4.65 p. (C C) 5.75;.t (acetate).

9,1 l-Seco-22a,25a-1 l-spirostyn-3B-ol-9-one EXAMPLE 4 Conversion of 4,5-seco-3-androstyn-l7B-ol-5-one to prepare testosterone and testosterone acetate Procedure 1 To a solution of 288 mg. of 4.5-seco-3- androstyn-17B-ol-5-one in 14 ml. of percent acetic acid add 75 mg. of mercuric acetate and 0.05 ml. of concentrated sulfuric acid. Heat the reaction mixture at reflux temperature for 1.8 hours under an atmosphere of nitrogen then cool to room temperature and add 50 m1. of water. Extract the reaction mixture with chloroform, then evaporate the combined chloroform extracts to a residue of 295 mg. comprising testosterone (4-androsten-l 7B-ol-3-one) and testosterone acetate. Separate the mixture by thin layer chromatography on two 8X8 inches X1 mm. Si GF plates using chloroform-ethylacetate solvent system. Identify the 3-acetate components by ultraviolet absorption, then elute from the Si-GF plates with acetone to obtain 167 mg. of testosterone acetate (product 4A) and 20 mg. of testosteronc (product 48). Recrystallize 4A from methylene chloride-ether and 48 from ether to obtain products having a melting point. infrared spectrum and thin layer chromatographic mobility identical to that of authentic samples thereof. Procedure 2 To a solution of 1 g. of 4,5-seco-3-androstyn-17B-ol-5-one (compound of Example 1) in 35 ml. of dioxane and 17 ml. of water add 0.1 g. of mercuric oxide and 0.3 ml. of trifluoroacetic acid. Stir the reaction mixture for one hour at room temperature, then add 400 ml. of water and ex- ,tract with chloroform. Wash the combined chloroform extracts with 2N hydrochloric acid, 15 percent aqueous sodium bicarbonate, and finally water. Dry the chloroform solution over sodium sulfate and evaporate in vacuo to 800 mg. of a residue comprising 4,5-secoandrostan-l7,B-ol-3,5-dione (compound 4C), a homogeneous product as determined by thin layer chromatography (Si GF with an ether solvent system). Purify by crystallization from ether; m.p. 112-113C [04],, 43 (CHCl )t 2.9 (OH) and 5.85 (C=O), nmr: 6.26.5 (C -H), 7.53 (C -OH), 7.83 (C.,3H); 8.89 (C -3H) and 9.20 'r (C -3H).

In a manner similar to that described in Example 63, treat 4,5-seco-androstan- 1 7B-ol-3,5-dione (compound 4C) with potassium tert.-butoxide in tcrt.-butanol. [solate the resultant product in a manner similar to that described to obtain testosterone (compound 48).

EXAMPLE 5 6,6-Dimethyl-4,5-seco-3-androstyn-17B-ol-5-one 1 7- methyl ether and 4,6,6-Trimethyl-4,5-seco-3-andros tyn- 1 7,8-01-5-one l7-methyl ether To a stirred solution of 1.8 g. of sodium hydride in 30 ml. of tetrahydrofuran under a nitrogen atmosphere add dropwise a solution of 2 g. of 4,5-seco-3-androstyn- 17B-ol-5-one (compound of Example 1) in 30 ml. of tetrahydrofuran. Heat the reaction mixture for 2 hours at 50C then cool to room temperature and add dropwise 12 ml. of methyl iodide. Heat the reaction mixture at 50C for 16 hours, cool to room temperature and decompose any excess sodium hydride with water. Add an additional 150 ml. of water then 150 ml. of ether and separate the organic layer from the aqueous layer. Wash the ethereal solution with water then dry over sodium sulfate and evaporate the ether in vacuo to a residue comprising 6,6-dimethyl-4,5-seco-3-androstyn- 17B-ol-5-one 17-methyl ether (compound 5A) and 4,6- ,6-trimethyl-4,5-seco-3-androstyn-17B-ol-5-one 17- methyl ether (compound 58). Purify and separate compounds 5A and 5 B as follows. Dissolve the residue in benzene and chromatograph on Merck acid washed alumina. Elute with benzene-hexane, combine the eluates and evaporate to a residue comprising 4,6,6- trimethyl-4,5-seco-3-androstyn-17B-ol-5-one 17- methyl ether (compound 5B). Purify by sublimation at 50C and mm Hg, lt 3.0, 4.7 and 5.9 u. nmr 6.7 (C17-O-CH 8.25 (doublet J 2 cps) (C.,CH 8.94 (C -CH 9.03 (2XC CH and 9.17 -r (C18 CH3)- Elute with benzene and evaporate the combined eluates to obtain 6.6-dimethyl-4,5-seco-3-androstyn-l7B- ol-5-one l7-methyl ether (compound 5A). Purify by crystallization from ethanol, m.p. 96-98C A 3.0, 4.7 and 5.9 M.- nmr 6.7 (C ,OCH 8.93 and 8.96 (C6 CH3), (C|9 CH3) and (C|9 CH3).

EXAMPLE 6 Conversion of 6,6-dimethyl-4,5-seco-B-androstyn- 17B-ol-5-onel7- methyl ether to 6,6-dimethyl testosterone 17-methyl ether A. 6,6-Dimethyl-4,5-seco-androstan-1713-01-3 ,5 dione To a slurry of 60 mg. red mercuric oxide and 0.1 ml. trifluoroacetic acid add a solution of 500 mg. 6,6- dimethyl-4,5-seco-3-androstyn-17fi-ol-5-one [7- methyl ether (compound 5A) in 50 ml. dioxane and 8 ml. water. Stir the reaction mixture for 2 hours at room temperature, then add 200 ml. water and extract with chloroform. Wash the combined chloroform extracts with saturated aqueous sodium bicarbonate solution, 3 percent hydrochloric acid, and finally with water. Dry the solution over sodium sulfate and evaporate in vacuo to a residue of 496 mg. comprising 6,6-dimethylili-seco-androstanl 7,B-ol-e,5-dione 17-methyl ether 7.97 (ECH;),

8.85 (C -CH 8.90 (C -CH 8.96 (C -CH and 9.171'(C CH B. 6,6-Dimethyl-testosterone l7-methyl ether (6,6- Dimethyl-4-androsten-l7B-ol-3-one 17-methy1 ether) To a solution of 227 mg. 6,6-dimethyl-4,5-secoandrostan-l7B-ol-3,5-dione 17-methyl ether (compound 6A) in 15 ml. dry t-butanol, add mg. potassium tertiary butoxide. Heat the reaction mixture at reflux temperature for 3 hours, then pour into ml. water. Acidify the aqueous solution with 3 percent hydrochloric acid, extract with chloroform, and wash the combined chloroform extracts with water. Dry the solution over sodium sulfate and evaporate in vacuo to a residue (175 mg.) comprising 6,6-dimethyltestosterone 17-methyl ether (compound 6B).

Purify by sublimation at C and 10 mm; m.p. 92-96C )t,,,,, 6.0 (C=O), 6.24 p. (C=C-), nmr: 4.07 (C H); 6.67 (OCH 6.66.9 (C -H), 8.70 (C -CH 8.82 and 8.86 (2 X C CH and 9.17 T(C13 'CH3).

EXAMPLE 7 4,5-Seco-3-androstyne-5B,17B-diol To a solution of 0.6 g. 4,5-seco-3-androstynel 7,8-01- 5-one in 80 ml. of methanol add 1.2 g. sodium borohydride. Stir the reaction mixture for one hour at room temperature then add an additional 1.2 g. of sodium borohydride and stir for an additional 16 hours at room EXAMPLE 8 6,6-Di-(2-propenyl)-4,5-seco-3-androstyn-l 7B-ol- -one A. 4,5-Seco-3 -androstyn-l 7,8-01-5-one tetrahydropyranyl ether To a solution of g. of 4,5-seco-3-androstyn-17B- ol-5-one in 30 ml. of dry benzene add 10 mg. of p-toluenesulfonic acid and 0.6 ml. of dihydropyran. Stir the reaction mixture for 2 hours at room temperature, then add water and separate the organic solution from the aqueous phase. When the organic solution with water then dry over sodium sulfate and evaporate the benzene and excess dihydropyran in vacuo to a residue comprising 4,5-seco-3-androstynl 7B-ol-5-one l7- tetrahydropyranyl ether.

Purify by chromatography on silica gel eluting with benzene. Distill the benzene from the combined eluates to a residue comprising 4,5-seco-3-androstyn-l7B-ol- 5-one l7-tetra-hydropyranyl ether, k 3.0 and 4.7 (C II CH) and 5.85 p. (C=O). This compound is used without further purification in the procedure of Example 8B. B. 6,6-Di-(2-propenyl)-4,5-seco-3-androstynl7B-ol-5-one l7-tetrahydropyranyl ether To a slurry of 3.2 g. of a 50 percent suspension of sodium hydride in mineral oil and 55 ml. of tetrahydrofuran, add dropwise a solution of 3.7 g. 4,5-seco-3- androstyn-l 7B-ol-5-one l7-tetra-hydropyranyl ether in 55 ml. of tetrahydrofuran. Heat the reaction mixture at reflux temperature for 2 hours under an atmosphere of nitrogen then cool to room temperature. Over a period of minutes add dropwise a solution of 5.2 g. 1,3- dibromopropane in 55 ml. of tetrahydrofuran. Heat the reaction mixture at reflux temperature for 18 hours, cool to room temperature, decompose any excess sodium hydride with water, then add 400 ml. of ether. Wash the ether solution with water and dry over sodium sulfate and remove the solvent in vacuo to a residue comprising 6,6-Di-(2'-propenyl)-4,5-seco-3- androstyn-l 7B-ol-5-one l7-tetrahydropyranyl ether. Purify by dissolving in benzene and chromatographing on 150 g. of Merck acid washed aluminum eluting with benzene-hexane. Distill the combined eluates to a resi- Prepare an analytical sample by sublimation at 10 mm and 80C. lt 3.0 and 4.7 (C I C-H), 3.25, 6.1, and 10.9

and 5.9 p. (C=O) 26 8.95 (C *3H), and 9.16 1'(C 3H).

C. 6,6-Di-( 2-propenyl)-4,5-seco-3-androstyn-l 7B-ol- 5-one To a solution of 0.26 g. of 6.6-(2-propenyl)-4,5-

seco-3-androstyn-l7B-ol-5-one in 12 ml. of methanol,

add 1.3 ml. of water followed by 0.5 ml. 12N hydrochloric acid. Stir the reaction mixture for 2 hours at room temperature, add 25 ml. of water and extract the solution with chloroform. Remove the chloroform from the combined extracts in vacuo to give 250 mg. of a residue comprising 6,6-di-(2'-propenyl)-4,5-seco-androstyn-l7B-ol-5 -one. Purify by sublimation at 10 mm Hg and C. lt 2.9 (OH) 3.0 and 4.7 (C I CH), 3.25, 6.1, and 10.9

r H (M and 5.9 ,u. (C=O).

EXAMPLE 9 Conversion of 6,6-di-(2-propenyl)-4,5-seco-3- androstynl 7,B-ol5 -one to 6,6-di-( 2-propenyl testosterone A. 6,6-Di-( 2-propenyl)-4,5-secol 7B-ol-3,5-dione To a suspension of 0.1 g. red mercuric oxide in 30 ml. of 20 percent aqueous dioxane containing 0.1 ml. of trifluoroacetic acid, add dropwise a solution of 1.0 g. 6,6- di-( 2'-propenyl )-4,5-seco-3-androstyn-l 7B-0l-5-one l7-tetrahydropyranyl ether in 30 ml. of 33 percent aqueous dioxane. Stir the reaction mixture for about 15 minutes and when the solution becomes cloudy add an additional 5 ml. of dioxane. Stir the reaction mixture at room temperature for an additional. 20 hours, then add 2 ml. of l2N hydrochloric acid and continue stirring for an additional 2 hours. Add the reaction mixture to 400 ml. of a saturated sodium chloride solution and extract four times with ml. portions of chloroform. Wash the combined chloroform extracts with water and dry over sodium sulfate and evaporate in vacuo to a residue (790 mg.) comprising 6,6-di-(2-propenyl)-4,5-secoandrostan-l7,B-ol-3,5-dione. Purify by dissolving in benzene and chromatographing on 25 g. of silica gel-G eluting with ether. Distill the eluates comprising 6,6-di- (2 -propenyl)-4,5-secol 7B-ol-3,5-dione (purified yield 600 mg.).

Prepare an analytical sample by sublimation at 10 mm at 80: [01],, 3; )i,,,,,,'"' 2.8 (OH), 3.0 and 4.7 (C- C-H) 3.25,'6.l and 10.9

and 5.9 p. (2 X C=O). I

B. 6,6-Di-( 2 -propenyl)-4-androsten-17B-ol-3-one (6,6-Di-(2-propenyl)-testosterone) To a solution of mg. of 6,6-di-(2'-propenyl)-4,5- seco-androstan-l7B-ol-3,5-dione in 15 ml. of t-butanol, add 50 mg. of potassium tertiary butoxide. Stir the reaction mixture at room temperature for 1.5 hours, at reflux temperature for 6 hours, at 40C for an additional 17 hours and then cool to room temperature. Add the reaction mixture to 50 ml. of water, neutralize with 2N hydrochloric acid and extract three times with 25 ml. portions of chloroform. Wash the combined chloroform extracts with water, dry over sodium sulfate and distill the chloroform in vacuo to a residue 129 mg.) comprising 6,6-di-(2-propenyl) 4-androsten- 17B-ol-3-one (6,6-di-(2'-propeny1)-testosterone). Purify by repeated crystallization from acetone; m.p. 196198C; [a],, 55 (Cl-1Cl A 2.85 (OH), 6.0 (C=O), 6.1 (C=C) and 6.23 and 10.9 p.

nmr 4.27 (4H); 4.83

5.1 (HC=C), 8.68 c -3n) and 9.18 c -an). 8 245 mp. (8700).

EXAMPLE 10 6,6-Pentamethylene-4,5-seco-3-androstyn-l 7B-ol- 5-one A. 6,6-Pentamethylene-4,5-seco-3-androstyn-17B- ol-5-one l7-tetrahydropyranyl ether To a stirred slurry of 0.43 g; of sodium hydride in 30 ml. of dry tetrahydrofuran under an atmosphere of nitrogen, add dropwise over a period of 10 minutes a solution of 2.2 g. of 4,5-seco-3-androstyn-l7B-ol-5-one l7-tetrahydropyranyl ether in tetrahydrofuran. Heat the reaction mixture at reflux temperature for two hours, then cool to room temperature and add dropwise over a period of ten minutes a solution of 1.38 g. of 1,5-dibromopentane in tetrahydrofuran. Heat the reaction mixture for 16 hours at 70C, cool to room temperature, then decompose the excess sodium hydride by the dropwise addition of water, then add 100 ml. of water followed by 100 ml. of ether. Wash the ethereal solution with water, dry over sodium sulfate, then remove the solvents in vacuo. Dissolve the resultant residue in benzene and chromatograph on 70 grams of Merck acid washed alumina eluting with hexane-benzene. Evaporate the eluates to a residue comprising 6,6-pentamethylene-4,5-seco-3-androstyn-17B- ol-S-one l7 -tetrahydropyranyl ether (yield 0.6- g.); A 3.0 (C OH), 4.7 (C I C) and 5.9 u (C=O).

This compound is used without further purification in i the procedure of Example 10B immediately following.

B. 6,6-Pentamethylene-4,5-seco-3-androstyn- 1 78-01- 5-one To a solution of 0.4 g. of 6,6-pentamethylene-4,5

seco-3-androstyn-17B-ol-5-one 1 7-tetrahydropyranyl ether in 20 ml. of 10 percent aqueous methanol add dropwise 0.5 ml. of 12N hydrochloric acid. Stir the reaction mixture for three hours at room temperature, then add 10 ml. of water and 10 ml. of chloroform. Extract the aqueous phase two additional times with 10 ml. portions of chloroform. Dry the combined chloroform extracts over sodium sulfate, then evaporate in vacuo. Dissolve the resulting residue in benzene and chromatograph on 12 g. of silica gel-6 eluting with a solution of 5 percent ether in benzene. Evaporate the eluates to a residue comprising 6,6-pentamethylene-4,5- seco-3-androstyn-l7B-ol-5-one (yield= 0.260 g.). Prepare an analytical sample by sublimation at 10 mm at 80C; A 2.9 (-OH), 3.0 and 4.7 (C I C-l-l); and

EXAMPLE 11 6,6-Pentamethylene-testosterone pentamethylene-4-androsten-17B-ol-3-one) A. 6,6-Pentamethylene-4,5-seco-androstan- 1 76-01- 3,5-dione To a slurry of 0.1 1 g. of red mercuric oxide in 20 ml. of dioxane containing 0.1 ml. trifluoroacetic acid, add dropwise a solution of 0.625 g. of 6,6-pentamethylcnc- 4,5-seco-3-androstyn-l7/3-ol-5-one in 15 ml. of 33 percent aqueous dioxane. Stir the reaction mixture for 5 hours at room temperature under an atmosphere of nitrogen, then pour into 200 ml. of water and extract sev eral times with 100 ml. portions of chloroform. Wash the combined chloroform extracts with a 5 percent aqueous sodium bicarbonate solution followed by a 2N hydrochloric acid solution, and finally with water. Dry

1 the chloroform solution over sodium sulfate, then remove the chloroform in vacuo to a residue (0.600 g.) comprising 6,6-pentamethylene-4,5-seco-androstan- 17B-ol-3,5-dione. Purify by crystallization from acetone. Prepare an analytical sample by recrystallization from acetone; m.p. ll2113C [a] 7(CHCl A 2.8 (-O1l) and 5.85 p. (C=O). nmr: 7.88 (C -3H); 8.92 (C -3H); 9.2 1- (C -3H).

B. 6,6-Pentamethylene-testosterone To a stirred solution of 0.300 g. of 6,6- pentamethylene-4,5 -seco-androstanl 7B-ol-3 ,5-dione in 30 ml. of t-butyl alcohol add 0.1 g. of potassium tertiary butoxide. Heat the reaction mixture at reflux temperature for 6 hours under an atmosphere of nitrogen and stir for an additional 16 hours at room tempera ture. Pour the reaction mixture into 100 ml. of water and neutralize the resulting solution with 2N hydrochloric acid, then extract with three ml. portions of chloroform. Wash the combined chloroform extracts with water, dry over sodium sulfate, then remove the chloroform in vacuo. Crystallize the resultant residue (0.227- g.) from acetone to give 6,6-pentamethylenetestosterone. Prepare an analytical sample by recrystallization from acetone; m.p. 181l83C; [01],, 121 (CHCl) A 2.8 (-O1-I), 6.0 (C=O), and 6.23p.(C=C); A 245 mp. (l4,400); nmr: 4.0 (C -H); 8.72 (C -3H); and 9.l8'r(C, -3H).

EXAMPLE 12 4,5-Seco-3-androstyne-5,17-dione and conversion thereof to 4-a ndrostene-3,17-dione A. 4,5-Seco-3-androstyne-5 ,17-dione To a stirred solution of 0.38 g. of 4,5-seco-3-androstyn-17B-ol-5-one in 20 ml. of acetone, add chromium trioxide until a permanent yellow color appears. Add the reaction mixture to 75 ml. of ice and saturated sodium chloride solution, then extract with three 50 ml. portions of ether. Wash the combined ether extracts with water, dry over sodium sulfate and distill in vacuo to a residue (0.33 g.) comprising 4,5-seco-3- androstyne-5,l7-dione. Purify by crystallization from ether. Prepare an analytical sample by recrystallization from ether; m.p. ll6-l 18C [11],, 99 (Cl-lCl A 3.0 (C I Cl-l), 4.7 (C I C), 5.8 (C=O), and 5.9 p. (C=O). nmr: 8.9 (C -3H) and 9.07 -r (C -3H).

B. 4Andr0stene-3,17-dione ln a manner similar to that described in Example 4 (Procedure I), treat 4,5-seco-3-androstyne-5,17-dione in acetic acid with mercuric acetate and concentrated sulfuric acid to obtain 4-androstene-3,l7-dione.

C. 4,5-Seco-'3-estryne-5,l7-dione .and conversion thereof to 4-estrene-3 l 7-dione in a manner similar to that described in Example 12A above, treat 4,5-seco-3-estryn-l7B-ol-5-one (the compound of Example 16) in acetone with chromium trioxide and isolate and purify the resultant product to obtain 4,5-seco-3-estryne-5,l7-dione (compound 12C) which in turn, upon treatment with mercuric acetate and concentrated sulfuric acid in acetic acid according to the procedure described in the above Example 128 is converted to 4-estrene-3,l 7-dione.

EXAMPLE l 3 tion with saturated aqueous sodium bicarbonate, then water and dry over sodium sulfate. Distill the solution in vacuo to a residue (1.18 g.) comprising 4,5-seco-- dehydro-3-androstyne-5',17B-diol diacetate. A 3.0 OH), 4.72 (C I C); 5.72 (enol acetate), 5.88 p. (acetate). nmr: 5.4 (C -H), 7.98 (2 X acetate), 8.92 (C -3H) and 9.l31-(C, -3H) This product is used without further purification in the following Example 13B.

B. 6,6-Dimethyl-4,5-seco-3-androstyn-l 7B-ol-5-one l7-acetate Into a dry nitrogen filled flask inject a solution of 12 ml. 1.6M n-butyl lithium in hexane. Evaporate the solvent in vacuo and to the residue add 5 ml. of dry ethylene glycol dimethyl ether in small portions, then add in 2 ml. portions a solution of 375 mg. of 4,5-seco-5- dehydro-3-androstyne-5,l7Bdiol diacetate in 10 ml. dry ethylene glycol dimethyl ether. Stir the reaction mixture at room temperature for 30 minutes then add 2 ml. of methyl iodide and stir the reaction mixture another 20 minutes. Stop the reaction by adding 3 percent hydrochloric acid to the solution, then dilute the two layers with ether and water. Wash the ether extract with aqueous sodium bicarbonate, then with water. Dry over sodium sulfate and evaporate in vacuo to a residue (376 mg.) comprising 6,6-dimethyl-4,5-seco-3-androstyn-l7B-ol-5-one l7-acetate in admixture with a trace of 6,6-dimethyl-4,5-seco-3-androstynl 7B-ol-5-one l7- methyl ether as detected by nmr and some starting material. Separate the starting material from the product mixture by chromatography on two 8 X 8-inch l-mm thick Si-GF plates (solvent system: benzene-ether (1:1)). 5 3.0 I C-H); 4.72 (C I C);

5.9 p. (-C=O). nmr: 5.4 (multiplet C -l-I); 7.96

(Ale...)

This product was used without further purification in 7 the procedure of Example 14A.

EXAMPLE 14 Conversion of 6,6-dimethyl-4,5-seco-3-androstynl7B-ol-5-one l7-acetate to 6,-dimethyl-testosterone A. 6 ,6-Dimethyl-4,5 -seco-androstanl 7,8-01-3 ,5 dione l7-acetate To a solution of 133 mg. of 6,6-dimethyl-4,5-seco-3- l0 androstyn-17B-ol-5-one l7-acetate containing a trace of 6,6-dimethyl-4,5-seco-3-androstyn-l 7B-ol-5-one l7- methyl ether (the product of Example [33) in 7 ml. of glacial acetic acid. add 40 mg. of mercuric acetate and 0.02 ml. of concentrated sulfuric acid. Heat the reac- 5 tion mixture to l C and stir at l 15C for 20 minutes.

then stir for another 40 minutes at room temperature.

F 11 9 rsaq qn m tu e tqwats n ex t the. resultant precipitate with ether. Wash the combined ether extracts with aqueous sodium bicarbonate, 3 percent hydrochloric acid, then water. Dry over sodium sulfate and distill the ether in vacuo to a residue (129 mg.) comprising 6,6-dimethyl-4,5-seco-androstan-17B- ol-3,5-dione l7-acetate containing a trace of 6,6- dimethyl-4,5 -seco-androstanl 7B-ol-3,5-dione l 7- methyl ether as detected by nmr. 6

5.9 ,u (C=O). nmr 5.4 (C -H),

' extract with chloroform. Wash the combined chloroform extracts with aqueous sodium bicarbonate solution, 3 percent hydrochloric acid, then water. Dry the chloroform solution over sodium sulfate, then remove the chloroform in vacuo to a residue (128 mg.). Chromatograph the residue on an 8 X 8-inch l-mm thick Si-GF plate utilizing benzene-ether as the solvent system. Elute the product comprising 6,6-dimethyl-4,5- seco-androstan-l7B-ol-3,5-dione in admixture with a trace of 6,6-dimethyl-testosterone from the Si-GF with chloroform. 'Yield 42 mg. 6 2.9 (OH);

6.0 ,u (C=O), nmr 4.15-4.50 (multiplet C -Hz),

8.84 (C -CH3); 8.89 (C CH 9.l7'r(C -CH This product was used in the following procedure 14C without further purification.

C. 6,6-Dimethyl-testosterone androsten- 1 7,8-ol-3-one) To a solution of 40 mg. of 6,6-dimethyl-4,5-secoandrostan-l7,8-ol-3,5-dione in admixture with a small quantity of 6,-dimethyl-testosterone (product of Example 14B) in 12 ml. of dry t-butanol add 50 mg. of potassium t-butoxide. Stir the mixture at 50C for 16 hours, then pour into 100 ml. of water, acidify the aqueous solution with 3 percent hydrochloric acid and extract with chloroform. Wash the combined chloroform extracts with water, dry over sodium sulfate and distill the chloroform in vacuo to a residue (39 mg.) comprising 6,6-dimethyl-testosterone. Purify by chromatography on an 8 X 8-inch l-mm thick Si-GF plate utilizing benzene-ether (1:1) as the solvent system. Elute the 6,6-dimethyl-testosterone from Si-GF with acetone (yield =25 mg.). Prepare an analytical sample by sublimation at 108 and 2 X 10 mm; m.p. 150l 56C [M 750.2". The infrared and nmr data for 6,6-dimethyl-testosterone are in agreement with data recorded in the literature (T. D. Y. DSilva and Howard T. Ringold. Tetrahedron Letters, No. 50, p. 4490 (1965).

8.96 (C -CH (6-6-dimethyl-4- EXAMPLE l5 Conversion of 4,5-seco-3-androstyn-l7B-ol-5-one l7-acetate to 6,6-dimethyl-testosterone A. 6,6-Dimethyl-4,5-seco-3-androstyn-17B-ol-5-one. 17-acetate Inject 25 ml. of 1.6Mn-butyl lithium in hexane into a dry nitrogen filled flask. Evaporate the hexane in vacuo and to the resultant semi-solid residue add in small portions 15 ml. of dry ethylene glycol dimethyl ether. Then add to this mixture in 3 ml. portions 500 mg. of 4,5-seco-3-androstyn-17B-ol-5-one 17-acetate (prepared by the action of 4,5-seco-3-androstyn-17B- ol-5-one in pyridine with acetic anhydride in a manner similar to the procedure of Example 18A) in 18 ml. of ethylene glycol dimethyl ether. Stir the solution at room temperature for 1.5 hours, then add 5 ml. methyl iodide and continue stirring for another 45 minutes. Add 20 ml. of 3 percent hydrochloric acid, then dilute the reaction mixture with ether and water to a total of 100 ml. Wash the ether extracts with-aqueous sodium bicarbonate, then water and dry over sodium sulfate. Distill the solvents in vacuo to a residue (610 mg.) comprising 6,6-dimethyl-4,5-seco-3-androstyn-l7B-ol- 5-one l7-acetate in admixture with a small quantity of 6,6-dimethyl-4,5-seco-3-androstyn-l7B-ol-5 -one 17- methyl ether. This product is identical to the product obtained in Example 13B as determined by thin layer chromatographic analysis, infrared and nmr spectral data. The product of this example is used without further purification in the following procedure Example 15B.

B. Alternate procedure of converting 6,6-dimethyl- 4,5-seco-3-androstyn-l7B-ol-5-one 17-acetate to 6,6- dimethyl-4,5-seco-androstan-17,8-01-3 ,S-dione 17-acetate To a slurry of 60 mg. red mercuric oxide in ml. dioxane add 0.1 ml. trifluoroacetic acid followed by a solution of 600 mg. 6,6-dimethyl-4,5-seco-3-androstyn- 17,B-ol-5-one 17-acetate mixed with the corresponding l7-methyl ether (i.e., the product of Example A) in 15 ml. of dioxane and 5 ml. of water. Stir the reaction mixture for 5.5 hours at room temperature, then pour into 200 ml. cold water, extract the resultant white suspension with three 50 ml. portions of chloroform. Wash the combined chloroform extracts with water, dry over sodium sulfate and evaporate in vacuo to a residue (537 mg.) comprising 6,6-dimethyl-4,5-secoandrostan-17,8-ol-3,5-dione l7-acetate in admixture with a small quantity of 6,6-dimethyl-4,5-secoandrostanl 7B-ol-3,5-dione l7-methyl ether. This product is identical to the product of Example 14A as determined by thin layer chromatographic data and spectroscopic data.

C. 6,-Dimethyl-testosterone androsten-17B-ol-3-one) Treat 6,6-dimethyl-4,5-seco-androstan-17B-ol-3 ,5 dione l7-acetate with potassium tertiary butoxide in t-butanol in a manner similar to that described in Ex- (6,6-dimethyl-4- ample 91316 obtain 6,6-dimethyl-testosterone in admix ture with a small quantity of the corresponding methyl ether, i.e., 6,6-dimethyl-testosterone methyl ether.

EXAMPLE 16' dium bicarbonate followed by dilute hydrochloric acid,

then water and dry over sodium sulfate and concentrate to a residue comprising 4,5-seco-3-estryn-17,8-01- '5-one.

Purify by chromatography on 250 g. of Florisil followed by elution with ether (5.2 g.). Upon further purification by crystallization from ether-hexane there is obtained an analytical sample of 4,5-seco-3-estryn- 17,8-ol-5-one.

89-90C. Amax-" l (chloroform) 5 (3280) (C I C-H; 2 (2120) (C E C);

5 p. (17 cm) (C=O) EXAMPLE l7 Conversion of 4,5-seco-3-estryn-l 7,8-ol-5-one to l9-nor-testosterone l7-acetate To a solution of 160 mg. of 4,5-seco-3-androstyn- 17/3-ol-5-one in 8 ml. of 90 percent acetic acid, add 42 mg. mercuric acetate and 0.03 ml. of concentrated sulfuric acid. Stir the resulting mixture under nitrogen at C for 90 minutes then pour into cold water. Extract the aqueous mixture with ether, wash the combined etheral extracts with aqueous sodium bicarbonate then dilute hydrochloric acid and finally with water. Dry over sodium sulfate and evaporate in vacuo to obtain a residue comprising l9-nor-testosterone l7-acetate. Thin layer chromatographic data and spectroscopic data of the product of this example is similar to that of an authentic sample of l9-nor-testosterone l7-acetate. 8,,,,,,""': 5.76 (l735)(OAc); 5.98 (1670)(C=O); 6.13 ,u. (1630 cm) (C=C).

EXAMPLE 1s Conversion of 4,5-seco-3-estryn-l 7B-ol-5-one to 6,6- dimethyl-4,5-seco-3-androstynl 7B-ol-5-one l7-acetate A. 4,5-Seco-3-estrynl 7,6-ol--one 17-acetate To a solution of 1.0 g. of 4,5seco-3-estryn-178-01- 5-onc (compound of Example 16) in 10 ml. of pyridine, add 1 ml. of acetic anhydride and leave at room temperature for 16 hours. Evaporate in vacuo to a small volume, then dissolve the residue in 100 ml. of ether. Wash the ether solution with water, dry over sodium sulfate and remove the ether in vacuo to a residue 1.1 g.) comprising 4,5-seco-3-estryn-l7B-ol-5-one l7-acetate. 5,,,.,,-"'"" 3.05 (C E C-H),

5.90 -c=0). nmr 5.2-5.6 c -11 7.98

9.11 T(c,., cr1

B. In a manner similar to that described in Example 15A, treat 4,5-seco-3-estryn l7B-ol-5-one l7-acetate with n-butyl lithium in ethylene glycol dimethyl ether followed by an excess of methyl iodide to obtain 6,6- dimethyl-4,5-seco-3-androstyn-17,8-01-5-one l7-acetate, which is identical to the compound obtained in Example 15A as determined by chromatographic and spectroscopic data.

EXAMPLE l9 Conversion of 4,5-seco-3-estryn-17B-ol 5-one to 6,6- dimethyl4,5-seco-3-androstynl 7B-ol-5-one 1 7- methyl ether in a manner similar to that described in Example 5 treat 4,5-seco-3-estryn-l7B-ol-5 one (compound of Example 16) with sodium hydride in tetrahydrofuran followed by an excess of methyl iodide to obtain 6,6-

dimethyl-4,5-seco-3-androstynl 7,8-ol-5-one 17- methyl ether.

EXAMPLE 2O 10B-n-Propyl-4,5-seco-3-estryn-l7,8-01-5-one A. 4,5-Seco-3-estryn-l 7B-ol-5-one 17- tetrahydropyranyl ether To a solution of 50 mg. of p-toluenesulfonic acid in 100 ml. dry benzene add a solution of 2.1 g. 4,5-seco-3- estryn-l7B-ol-5-one (compound of Example 16) in 100 ml. dry benzene. To this mixture add 1 ml. dihydropyran in one portion. Stir the reaction mixture for one hour at room temperature then wash with water and dry over sodium sulfate. Evaporate the benzene in vacuo to a residue (2.6 g.) comprising 4,5-seco-3- estryn-l7B-ol-5-one l7-tetrahydropyranyl ether (i.e., l7-OT1-1P) k 3.04 OH), 4.70 (C E C-), 5.85 p.(C=O). nmr 5.25-5.50, 5.85-6.75 (OTHP and C H), 9.13 and 9.151 (C -CH B. l0,B-n-Propyl-4,5-seco3-estrynl 7B-ol-5-one 17- tetrahydropyranyl ether To a slurry of 3 g. of 62.4 percent sodium hydride (in mineral oil) in 30 ml. dry tetrahydrofuran add in one portion a solution of 1.54 g. 4,5-seco-3-estryn-l7B-ol- 5-one l7-tetrahydropyranyl ether in 45 ml. dry tetrahydrofuran. Stir the reaction mixture at room temperature under a nitrogen atmosphere for 1.5 hours, then add 0.42 ml. n-propyl iodide. Stir the reaction mixture at room temperature for 16 hours, then heat at reflux temperature for 1.5 hours. Decompose the excess sodium hydride by adding 25 ml. of water, then dilute the reaction mixture with 150 ml. of ether, separate the layers and wash the organic layer with water. Dry the organic solution over sodium sulfate, then remove the solvent in vacuo, chromatograph the resultant residue on 200 g. of Florisil eluting with 5 percent ether. Evaporate the ether from the combined eluates to a residue (471 mg.) comprising 10B-n-propyl-4,5-seco. 3-estryn- 17B-ol-5-one l7-tetrahydropyranyl ether. A 3.0 C-H); 4.7 (C HE C); 5.85 .11. (C=O). This product was used without further purification in the following procedure of Example 20C.

C. 10B-n-Proply-4,5-seco-3-estryn-17B-ol-5-one To a solution of 470 mg. 10B-n-propyl-4,5-seco-3- estryn-l7B-ol-5-one l7-tetrahydropyranyl ether in 40 ml. 90 percent aqueous methanol, add 2 ml. concentrated hydrochloric acid and stir the mixture at room temperature for 1.5 hours. Pour the reaction mixture into cold water (25C) and extract the resulting white suspension into chloroform. Wash the combined chloroform extracts with aqueous sodium bicarbonate, then water and dry over sodium sulfate. Evaporate the solvent in vacuo to a residue (270 mg.) comprising IOB-npropyl-4,5-seco-3-estryn-17B-ol-5-one )t,,,,,,"" 2.9 (01-1), 3.0 C-l-l), 4.7 (C I C), 5.88-5.95 1. (broad c=o nmr 6.35 (C -H); 9.16 T (C -CH propyl- Cl-l shoulder). This product is used without further purification in the procedure of Example 21A.

EXAMPLE 21 ll (broad. C-CH;

and C=O). nmr 6.4 (C -H), 7.19 (C -acetate),

i 7.84 CCHa 9.18 c -c11 9.12 7' (center of propyl CH triplet). This product was used without further purification for t prosedure 9.0 1 w n Examp e 211% B. l0B-n-Propyl-4-estren-l 7B-ol-3-one Treat 10B-n-propyl-4,5-seco-estran-l 7B-ol-3 ,5 -dione with t-butoxide in t-butanol and isolate the resultant product in a manner similar to that described in Example 68 to obtain l0B-n-pr0pyl-4-estren-l7B-ol-3-one. Purify the product by chromatography on 8 X 8 inch 1 mm thick Si-GF plate utilizing as solvent system chloroform-ethyl acetate (1:1). Extract the l0B-n-propyl-4- estren-l7B-ol-3-one from the Si-GF with chloroform, evaporate the chloroform and crystallize the resultant product from methylene chloride-hexane. To obtain an analytical sample recrystallize several times from methylene chloride-hexane, mp. -151C; A 2.9 (0H), 6.02 (C=O), 6.20 11 (C=C). nmr 4.20 (C -H). 6.35 (C -H), 4.7 (OH), 9.19 -r (C -CH EXAMPLE 22 Conversion of In a manner similar to that descirbed in Example 20B, treat 4,5-seco-3-estryn-l7,8-01-5-one 17- tetrahydropyranyl ether (compound of Example 20A) with sodium hydride in reluxing tetrahydrofuran for 12 hours followed by treatment with an excess of 3- bromo-l-propene. (This procedure is carried out in refluxing tetrahydrofuran, whereas the procedure of Example 20B is carried out at room temperature.) Isolate the resultant product in a manner similar to that described in Example 208 to obtain 6,10,8-di-(2- propenyl)-4,5-seco-3-estryn-17B-ol-5-one l7- tetrahydropyranyl ether. Purify by chromatographing on silica gel eluting with benzene-ether (20: 1) and distilling the combined eluates to give 6,IOB-di-(2- propenyl )-4,5-seco-3-estrynl 7,8-ol-5-one 1 7- tetrahydropyranyl ether. h 3.0 (s C-H), 4 7() (C E C), 5.78 (C=O), 3.25, 6.1, 10.9 ,u.

(Emits;

5.25 5.50, 5.85 6.75 (OTHP, C -H), 9.11 and 9.13 -r(C -CI-I EXAMPLE 23 Conversion of 6,10B-di-(2-propenyl)-4,5-seco-3- estryn-17/3-ol-5-one I7-tetrahydropyranyl ether to 6,1- OB-di-( 2 -propenyl)-4-estren-17,8-ol-3-one A. 6,10,8-Di-(2'-propenyl)-4,5-seco-estran-1 7B-ol- 3,5-dione In a manner similar to that described in Example 9A, treat 6, 10B-di-(2'-propenyl)-4,5-seco-3-estryn-l 7B-ol- 5-one l7-tetrahydropyranyl ether (compound of Example 22A) with mercuric oxide and trifluoroacetic acid in 90 percent aqueous dioxane followed by treatment with 12N hydrochloric acid to obtain 6,10B-di- (2 '-propenyl)-4,5-seco-estran-17B-ol-3,5-dione. Purify the resultant product, isolate in the manner described in Example 9A by chromatography on Florisil eluting with benzene-ether (1:3) and distill the eluates in vacuo to a residue comprising 6,10B-di-(2-propenyl)- 4,5seco-estran-l7B-ol-3,5-dione. Prepare an analytical sample by sublimation at 105 and 2 X 10 mm. Product is an oil. [a] =28.5 A 2.9 (OH), 5.88 (2 C=O), 3.22, 6.10, 10.9 p.

6.35 (CH-H); 7.88

(CCHa) 9.17 1- (C -CH B. 6,lOB-Di-(2-propenyl)-4-estren-17B-ol-3-one In a manner similar to that described in Example 98, treat 6,l0-di-(2-propenyl)-4,5-seco-estran-173-01-35- dione with potassium tertiary butoxide in t-butanol to obtain 6,10-di-(2-propenyl)-4-estren-l7B-ol-3-one.

Isolate the resultant product in a manner similar to that described in Example 913 and purify by thin layer chromatography on 8 X 8 inch 1 mm Si-GF plates utilizing as solvent system chloroform-ethyl acetate (1:1) to give 6,1OB-di-(2-propenyl)-4-estren-17,8-01-3-one. The product is an oil. [01],, l8.7 2.9 (01-1), 5.9-6.1 (broad C=O), 3.25, 6.24, 10.9

nmr 4.13 (C I-I), 4.84, 4.87

6.35 (C -H), 7.24 (C -OH); 9.18 'r(C -CH A. 6,6,10B-Tri-(2-propenyl)-4,5-seco-3-estryn-17,8- ol-S-one l7-tetrahydropyranyl ether To a slurry of 1.8 g 62.4 percent sodium hydride (in mineral oil) in 20 ml. dry tetrahydrofuran, add a solution of 840 mg. of 6,l0B-di-(2'-propenyl)-4,5-seco-3- estryn-l7B-ol-5-one 17-tetrahydropyranyl ether in 40 ml. tetrahydrofuran. Stir the mixture at room temperature for 24 hours, then add 14 ml. of 3-bromo-1- propene and then heat the reaction mixture at reflux temperature for 72 hours. Add 50 ml. of water dropwise at first, to decompose excess sodium hydride, then extract the oily suspension with chloroform. Wash the combined chloroform extracts with water, dry over sodium sulfate and evaporate in vacuo to a residue (1.44 g., containing mineral oil). Dissolve the residue in benzene and chromatograph on 40 g. silica gel eluting with benzene-ether (9:1). Evaporate the combined eluates to a residue (884 mg.) comprising 6,61OB-tri-(2- propenyl)-4,5-seco-3-estryn-17B-ol-5-one 17- tetrahydropyranyl ether as an oil. A 2.98 C-H), 5.92 (C=O), 3.22, 6.08, 10.95 p.

nmr 4.9 and 4.0 5.25 (6 protons 5.25 5.50, 5.58 6.75 (OTI-IP, C -H); 9.11 5-85 9.13 T (C -CH b. 6,6,1OB-Tri-(2'-propenyl)-4,5-seco-estran-l76-01- 3,5-dione In a manner similar to that described in Example 9A, treat 6,6,10B-tri-(2-propenyl)-4,5-seco-3-estryn-l7B- ol-5-one 17-tetrahydropyranyl ether with mercuric oxide and trifluoroacetic acid in 90 percent aqueous dioxane followed by treatment with 12N hydrochloric acid. Isolate the resultant product in a manner similar to that described to obtain 6,6,l0,B-tri-(2'-propenyl)- 4,5 -seco-3-estranl 7/3-01-3 ,5-dione. Purify by chromatographing the residue on silica gel eluting with benzene-ether (20:1). Evaporate the combined eluates to a residue comprising 6,6,lOB-tri-(Z-propenyl)-4,5- seco-estran-l7B-ol-3,5-dione. Prepare an analytical sample by sublimation at 110C and 2 X mm Hg to obtain an oil. [01],, -7.1 )1 3.0 (OH); 5.85.95

nmr4.88 and 4.0 5.25 (9 protons O (-&CH)

EXAMPLE 25 Conversion of 4,5-seco-3-estryn-17B-ol-5-one l7- tetrahydropyranyl ether to 10,8-dodecyl-4-estren-17B- ol-3-one A. 6-Formyl-4,5seco-3-estryn-17B-ol-5-one tetrahydropyranyl ether To a solution of 3.1 g. of 4,5-seco-3-estryn-1713-01- 5-one l7-tetrahydropyranyl ether (the compound of Example A) in 125 ml. of benzene, add in three portions 6.4 g. sodium methoxide in 125 ml. benzene. Cool the reaction mixture in a cold water bath and add dropwise an excess ml.) of ethyl for-mate. Stir the reac tion mixture for three hours, then dilute the solution with benzene to a volume of 200 ml. and extract with four 100 ml. portions of 4 percent aqueous sodium hydroxide. Acidify the combined basic extracts with 3 percent aqueous hydrochloric acid. Extract the resultant precipitate into 300 ml. chloroform then wash the combined chloroform extracts with three 150 ml. portions of water. Dry the chloroform solution over sodium sulfate and evaporate in vacuo to a residue (2.85 g.) comprising 6-formyl-4,5-seco-3-estrynl 7B-ol- 5-one l7-tetrahydropyranyl ether. A 3.0 E C-H); 4.7 (-C C-), 6.1 (broad C=O); 6.3 p. (broad C=O). This compound is used without further purification in the reaction of Example 25B immediately following.

B. 6-n-Butylthiomethylene-4,5-seco-3-estryn-17,8-01- 5-one 17-tetrahydropyranyl ether To a solution of 2.85g. 6-formyl-4,5-seco-3-estryn- 17B-ol-5-one l7-tetrahydropyranyl ether in 150 ml. of benzene, add 60 mg. p-toluenesulfonic acid and 1.5 ml. n-butyl mercaptan. Heat the reaction mixture at reflux temperature for 3 hours and continuously remove water by means of a Soxhlet extractor utilizing calcium 9.17 1(C -CH carbide as drying agent. Cool the reaction mixture to room temperature, dilute with benzene to a volume of 250 ml., then wash the benzene solution three times with aqueous sodium bicarbonate solution and then 5 withwater. Dry the benzene solution over sodium sulfate and remove the solvent in vacuo to a residue (3.14

g.) comprising 6-n-butylthiomethylene-4,5-seco-3- estryn-l7B-ol-5-one in admixture with the corresponding 17-tetrahydropyranyl ether. Convert the product to lo the tetrahydropyranyl ether by treatment thereof with dihydropyran in benzene in the presence of p-toluenesulfonic acid in a manner described in Example 20A. Isolate the product in the manner described and purify by chromatography on 200 g. Florisil eluting first with benzene-ether (50:1) and then with benzene-ether (25:1). Evaporate the combined eluates to a residue (1.1 g.) comprising 6- n-buty1thiomethylene-4,5-seco- 3-estryn-17B-ol-5-one 17-tetrahydropyranyl ether as 20 an oil. A fl'" 3.0 C-H); 4.7 (C C); 6.05 p.

(C=O). nmr 2.67

sBn La.

5.30 5.60, 5.85 6.85 (OTHP, C, -H); 9.18 and 9.20 r (C -CH This compound is used without further purification in the reaction of Example 25C immediately following.

C. fi-(n-Butylthiomethylene)-lOB-(n-dodecyl)-4,5- seco-3-estrynl 7B-ol-5-one To a solution of 1.41 g. of 6-(n-butylthiomethylene)- 4,5-seco-3-estrynl 7B-ol-5-one l7-tetrahydropyranyl ether in 120 ml. dry t-butanol, add 700 mg. potassium tertiary butoxide in three portions. Stir the reaction mixture at room temperature for 30 minutes, then add 15 ml. n-dodecyl iodide in one portion. Stir the mixture for 36 hours at 50C, then pour into 300 ml. water. Extract the resulting suspension into chloroform and wash the combined chloroform extracts with water, dry over sodium sulfate and remove the solvent in vacuo to a residue. Chromatograph the residue on 150 g. of Florisil eluting with hexane (to remove the excess n-dodecyl iodide) followed by benzene-ether (9:1). Evaporate the combined benzene-ether eluates to a residue (270 mg.) comprising 6-( n-butylthiomethylene 1 0B-( n- -dodecyl)-4,5seco-3-estryn-l 7B-0l-5-one, as an oil. 2.9 (OH); 3.0 C-H); 4.7 (C I C); 6.05 p.

AIIIGI S Bu (C=O). nmr 2.67 

1. THE FIRST PREFERRED PROCESS COMPRISES THE PREPARATION OF 5-KETONE-4,5-SECO-3-YNE STEROIDS FROM 3-KETO-4-DEHYDRO STEROIDS HAVING A TERTIARY CARBON AT C-3, VIA THE 3HYDROCARBONSULFONYLHYDRAZONO-4,5-OXIDO DERIVATIVE THEREOF WHICH UNDERGOES FISSION AND RERRANGEMENT IN SITU TO FORM THE 5-KETO-4,5-SECO-3-YNE STRUCTURE;
 1. BY REACTION WITH MERCURIC ACETATE AND SULFURIC ACID IN ACETIC ACID; OR
 2. BY REACTION WITH MERCURIC OXIDE AND TRIFLUORACETIC ACID FOLLOWED BY TREATMENT OF THE THEREBY FORMED 3,5-DIKETO4; 5-SECO STEROID WITH POTASSIUM T-BUTOXIDE IN T-BUTANOL
 2. THE SECOND PREFERRED PROCESS COMPRISES REACTING ANY 6AND/OR 10- SUBSTITUTED-5-KRTO-4,5-SECO-3-YNE IN AN ALKYLATING MEDIUM WITH A HYDROCARBON SULFONATE OR, PREFERABLY, AHYDROCARBON HALIDE TO FORM A 6-AND/OR 10HYDROCARBON SUBSTITUTED-5-KETO-4,5-SECO-3-YNE; AND
 2. A process according to claim 1 wherein said 3-keto-4-dehydro-steroid of the pregnane, androstane and estrane series is a compound having the following structural formula A:
 3. THE THIRD PREFERRED PROCESS COMPRISES TREATING A 5-KETO4,5-SECO-3-YNE WITH AN ALKALI METAL BOROHYDRIDE TO FORM A 5-HYDROXY-4,5-SECO-3-YNE. ALSO DESCRIBED IN DETAIL (INCLUDING EXAMPLES) ARE TWO METHODS WHREBY THE PREFERRED 5-KETO-4,5-SECO-3-YNES OF THIS INVENTION ARE CONVERTED TO PHARMACOLOGICALLY VALUABLE 6AND/OR 10- HYDROCARBON SUBSTITUTED-3-KETO-4-DEHYDRO STEROIDS, E.G.,
 3. The process according to claim 2 wherein said epoxidizing reagent is aqueous alkaline hydrogen peroxide and said hydrocarbonsulfonylhydrazine is a member selected from the group consisting of p-toluenesulfonylhydrazine and methanesulfonyl-hydrazine.
 4. The process according to claim 2 wherein said 3-keto-4-dehydro-steroid is 4-androsten-17 Beta -ol-3-one, said epoxidizing agent is m-chloroperbenzoic acid, and said hydrocarbonsulfonylhydrazine is p-toluenesulfonylhydrazine in a lower alkanol having up to 4 carbon atoms, said process comprising reacting 4-androsten-17 Beta -ol-3-one with p-toluene-sulfonylhydrazine in a lower alkanol having up to 4 carbon atoms followed by treatment of the thereby formed 3-p-toluenesulfonyl-hydrazono-4,5-oxido-4-androsten-17 Beta -ol-3-one with m-chloroperbenzoic acid whereby is produced 4,5-seco-3-androstyn-17 Beta -ol-5-one.
 5. The process according to claim 1 wherein said 3-keto-4-dehydro-steroid is 17 Alpha ,20-isopropylidenedioxy-4-pregnen-3-one, said epoxidizing reagent is alkaline hydrogen peroxide, and said hydrocarbonsulfonylhydrazine is p-toluenesulfonylhydrazine in ethanol; said process comprising reacting 17 Alpha ,20-isopropylidene-dioxy-4-pregnen-3-one with alkaline hydrogen peroxide, and reacting the thereby formed 4,5-oxido-17 Alpha ,20-isopropylidenedioxy-pregnane-3-one with p-toluenesulfonylhydrazine in ethanol, whereby is produced 17 Alpha ,20-isopropylidene-dioxy-4,5-seco-3-pregnyn-5-one.
 6. The process according to claim 2 wherein said 3-keto-4-dehydro-steroid is a member selected from the group consisting of 17 Alpha ,20;20,21-bismethylene-dioxy-4-pregnen-3-one and the 11-keto analog thereof, said epoxidizing reagent is alkaline hydrogen peroxide and said hydrocarbonsulfonylhydrazine is p-toluenesulfonylhydrazine in n-propanol; said process comprising reacting a member of the group comprising 17 Alpha ,20;20,21-bismethylenedioxy-4-pregnen-3-one and the 11-keto analog thereof with alkaline hydrogen peroxide and reacting the thereby formed corresponding 4,5-oxido derivative with p-toluenesulfonylhydrazine in n-propanol whereby is produced a member selected from the group consisting of 17 Alpha ,20;20,21-bismethylenedioxy-4,5-seco-3-pregnyn-5-one and the 11-keto analog thereof.
 7. A process for the preparation of a 5-keto-4,5-seco-3-yne steroid of the group consisting of the pregnane, androstane and estrane series which comprises treating a 3-keto-4,5-oxido-steroid of the group consisting of the pregnane, androstane and estrane series with a hydrocarbonsulfonylhydrazine having up to 10 carbon atoms.
 8. A process according to claim 7 wherein said hydrocarbonsulfonylhydrazine is a member selected from the group consisting of methanesulfonylhydrazine and p-toluenesulfonylhydrazine.
 9. A process according to claim 7 wherein said 3-keto-4,5-oxido-steroid is a member selected from the group coNsisting of 4,5-oxido-estran-17 Beta -ol-3-one and 4,5-oxido-androsten-17 Beta -ol-3-one and there is formed a member selected from the group consisting of 4,5-seco-3-estryn-17 Beta -ol-5-one and 4,5-seco-3-androstyn-17 Beta -ol-5-one.
 10. A process for the preparation of an Alpha -keto- Alpha , Beta -seco- Beta ( gamma )-yne steroid of the group consisting of the pregnane, androstane and estrane series which comprises reacting an Alpha -keto- Beta -dehydro steroid of the group consisting of the androstane, pregnane and estrane series with para toluenesulfonylhydrazine and with an epoxidizing reagent of alkaline hydrogen peroxide whereby the thereby formed Alpha -para toluenesulfonylhydrazono- Beta , gamma -oxido-steroid fragments and rearranges in situ to produce said Alpha -keto-Alpha , Beta -seco- Beta ( gamma )-yne steroid of the pregnane, androstane and estrane series. 